RESEARCH REPORT 2014 | 2015 · erforscht die Kommunikation zwischen Bakteri-en und Eukaryoten....

RESE ARCH REPORT

2014 | 2015

RESEARCH REPORT 2014 | 2015

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VORWORTNeben der inhaltlichen und strukturellen Weiter-entwicklung des Instituts stand 2014 und 2015 vor allem die interdisziplinäre Vernetzung mit der Friedrich-Schiller-Universität Jena (FSU) und weiteren Forschungseinrichtungen im Fokus, sodass wir gemeinsam das internationale Re-nommee des Standorts Jena im Bereich der mi-krobiologischen Forschung verstärken konnten.

Wir freuen uns, dass gleich zwei Nach-wuchsgruppen ihre Arbeit am HKI aufnahmen: Die Chemikerin Dr. Christine Beemelmanns be-gann mit ihrem Team die Wechselwirkungen zwischen Bakterien, Pilzen und Insekten sowie die daran beteiligten Naturstoffe zu untersu-chen. Dr. Pierre Stallforth, ebenfalls Chemiker, erforscht die Kommunikation zwischen Bakteri-en und Eukaryoten. Beide Forschergruppen be-reichern unser Institut vor allem im Bereich der Naturstoff-Forschung.

Besonders erfreulich ist die Berufung des HKI zum Nationalen Referenzzentrum für Inva-sive Pilzinfektionen durch das Robert Koch-Ins-titut und das Bundesministerium für Gesundheit. Die Expertise im Feld der Pilzinfektion ist in Jena so gebündelt wie an kaum einem anderen Ort: Mit dem Fachwissen unserer Wissenschaftler sind wir in Kooperation mit der FSU, dem Uni-versitätsklinikum Jena sowie dem Zentrum für Innovationskompetenz Septomics ein kompe-tenter Ansprechpartner für Ärzte und Mikrobio-logen aus ganz Deutschland.

Mit allen Aspekten von Infektionen und ihrer Be-kämpfung beschäftigt sich auch das vom HKI initiierte und koordinierte Konsortium InfectCon-trol 2020. In den Jahren 2014/15 begannen un-ter dem Dach von InfectControl 2020 zahlreiche Verbundvorhaben mit Partnereinrichtungen aus ganz Deutschland. Der Schwerpunkt liegt dabei auf Forschungseinrichtungen und Unterneh-men aus dem Osten Deutschlands. In der Strate-giephase steckten die beteiligten Wissenschaft-ler und Industriepartner wichtige Problemfelder ab und definierten in einem Statusworkshop drei Basisprojekte.

Mit dem SFB ChemBioSys der Universität Jena ging bereits der zweite Sonderforschungs-bereich mit wesentlicher Beteiligung des HKI an den Start. Gemeinsam mit dem mit der Univer-sität Würzburg initiierten SFB/Transregio Fungi-Net wird damit die Spitzenforschung im Bereich Mikrobiologie am Standort Jena zielstrebig stra-tegisch ausgebaut.

Gemeinsam mit dem Leibniz-Institut für Photonische Technologien, der Friedrich-Schil-ler-Universität, dem Universitätsklinikum, der Ernst-Abbe-Hochschule und weiteren außeruni-versitären Instituten initiierten wir zudem den Leibniz ScienceCampus InfectoOptics“, der sich der Erforschung von Infektionskrankheiten mit neuen optischen Methoden widmet. Auch der im Rahmen des BMBF-Programms Biotechnologie 2020+ neu gegründete Leibniz Research Cluster verbindet Lebens- und Ingenieurwissenschaf-ten. Gemeinsam mit vier weiteren Leibniz-Ins-tituten entwickeln wir neue biotechnologische Methoden für die Produktion von Wirkstoffen.

Im Zuge der interdisziplinären Zusammen-arbeit ist es essenziell, sich persönlich auszu-tauschen und Kontakte zu knüpfen: Aus diesem Grunde richteten wir unter anderem die gemein-same Konferenz der Deutschsprachigen Myko-logischen Gesellschaft und des SFB/Transregio FungiNet aus. Auf einem vom HKI ausgerich-

HKI RESEARCH REPORT 2014 | 2015 03

teten Biotechnologie-Symposium diskutierten deutsche und US-amerikanische Experten au-ßerdem über die Zukunft der Wirkstoffsuche und -entwicklung und verstärkten die Brücke zwischen Wirkstoff-Forschung und Industrie.

Insbesondere die transdisziplinären Koope-rationen führten uns in den Jahren 2014 und 2015 zu großen wissenschaftlichen Erfolgen, die auch international aufmerksam wahrge-nommen wurden. Gulimila Shabuer, Dokto-randin in der Abteilung Biomolekulare Chemie, landete zum Beispiel einen besonderen Clou in Zusammenarbeit mit australischen Kolle-gen: Die Forschergruppe entdeckte eine neue Strategie des eigentlich Sauerstoff-empfindli-chen Kartoffelschädlings Clostridium puniceum. Dabei detektierten die Wissenschaftler eine neue Gruppe von Wirkstoffen, die Clostrubine, die antibiotisch gegen andere Krankheitserre-ger wirken. Die Forschergruppe veröffentlichte die Ergebnisse im renommierten Fachjournal Science und wurde hierfür mit dem medac-For-schungspreis ausgezeichnet.

Neben ca. 330 weiteren Publikationen bestä- tigen erneut zahlreiche Preise und Auszeich-nungen die Qualität und Bedeutung unserer For-schung. Ganz besonders gratulieren wir Chris-tian Hertweck zum Leibniz-Preis der DFG. Die wichtigste Auszeichnung für Wissenschaftler in Deutschland bestätigt seine wissenschaftliche Reputation, von der Jena als Wissenschafts-standort und insbesondere das HKI profitieren. Die ehrenvolle European Academy of Microbiolo-gy wählte Axel Brakhage als neues Mitglied und würdigte damit seine Arbeiten auf dem Gebiet der Diagnose und Therapie von lebensbedrohen-den Pilzinfektionen. Die Deutsche Gesellschaft für Hygiene und Mikrobiologie (DGHM) zeichne-te Axel Brakhage und Bernhard Hube gemein-sam mit dem DGHM-Hauptpreis aus – einer der wichtigsten Auszeichnungen auf dem Gebiet der medizinischen Mikrobiologie. Darüber hin-

aus durften sich Christine Skerka und Peter F. Zipfel über den Galenus-von-Pergamon-Preis für ihre Erkenntnisse zur schweren Nierenerkran-kung Dense Deposit Disease freuen. Das vom Team um Christian Hertweck entdeckte Mole-kül Closthioamid wurde zum Leibniz-Wirkstoff des Jahres 2014 gewählt. Zu großem Dank sind wir weiterhin der medac AG verpflichtet. Das Unternehmen stiftet seit vielen Jahren den me-dac-Forschungspreis, mit dem kooperative For-schungsprioekte am HKI ausgezeichnet werden, die sich in besonders hochrangigen Publikatio-nen niederschlugen.

Auch die Arbeit der nachwachsenden For-schergeneration wurde mit renommierten Aus-zeichnungen belohnt: Unser Doktorand Tom Bretschneider erhielt den Nachwuchspreis der Leibniz-Gemeinschaft für seine Erkenntnisse über die Biosynthese des Naturstoffes Rhizoxin. Qian Chen und Florian Kloß wurden für ihre her-vorragenden Promotionsarbeiten mit einem Pro-motionspreis der Friedrich-Schiller-Universität Jena und dem Nachwuchspreis des Beutenberg Campus e. V. ausgezeichnet.

Rückblickend möchte ich noch auf das her-vorragende Ergebnis der Evaluierung des HKI aufmerksam machen. Der Senat der Leibniz-Ge-meinschaft bescheinigte dem HKI in seiner abschließenden Stellungnahme eine internati-onale Spitzenstellung auf den wissenschaftlich äußerst relevanten Themenfeldern der Natur-stoff- und Infektionsforschung. Diese sehr gute Bewertung ist vor allem der großen Motivation und der kollegialen Zusammenarbeit aller Mitar-beiterinnen und Mitarbeiter zu verdanken. Und dafür danke ich der gesamten Belegschaft.

Axel Brakhage, Direktor HKI

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INTRODUCTIONIn 2014 and 2015, in addition to the further de-velopment of the Institute's research topics and structure, the main focus in was on interdiscipli-nary networking with the Friedrich Schiller Uni-versity Jena (FSU) and other research institu-tions. Thus, together we were able to strengthen the international reputation of Jena in the field of microbiological research.

We are pleased that two junior research groups took up their work at the HKI: The chem-ist Dr. Christine Beemelmanns and her team be-gan to investigate the interactions between bac-teria, fungi and insects and the natural products involved. Dr. Pierre Stallforth, also a chemist, is investigating the communication between bac-teria and eukaryotes. Both research groups en-rich our institute especially in the field of natural product research.

We are particularly happy about the ap-pointment of the HKI as the National Reference Center for Invasive Fungal Infections by the Robert Koch Institute and the Federal Ministry of Health. The concentration of expertise in the field of fungal infections in Jena is unique: With the expertise of our scientists in cooperation with the FSU, the University Hospital Jena and the Center for Innovation Competence Septom-ics, we are a competent partner for physicians and microbiologists from all over Germany.

The InfectControl 2020 consortium initi-ated and coordinated by the HKI deals with all aspects of infections and their control. 2014/15 saw the start of numerous collaborative projects with partner institutions from all over Germany under the umbrella of InfectControl 2020, with a focus on research institutions and compa-nies from eastern Germany. During the strategy phase, the scientists and industry partners iden-tified important problem areas in a status work-

shop and defined three core projects to address these questions.

The CRC ChemBioSys at the University of Jena is the second Collaborative Research Centre with significant participation of the HKI. Together with the CRC/Transregio FungiNet, which was initiated jointly with the University of Würzburg, we are thus purposefully and strategi-cally expanding top-level research in the field of microbiology in Jena.

Together with the Leibniz Institute of Photon-ic Technology, the Friedrich Schiller University, the University Hospital Jena, the Ernst Abbe University and other non-university institutes, we also initiated the "Leibniz ScienceCampus InfectoOptics", which is dedicated to research into infectious diseases using new optical meth-ods. The Leibniz Research Cluster, newly found-ed as part of the BMBF's Biotechnology 2020+ programme, also brings together life scientists and engineers. Together with four other Leibniz Institutes, we are developing new biotechnologi-cal methods for the production of active com-pounds.

For effective interdisciplinary cooperation, it is essential to exchange ideas and make per-sonal contacts: For this reason, we organised the joint conference of the German-speaking Mycological Society and the CRC/Transregio FungiNet as well as several other scientific meetings. At the biotechnology symposium organised by the HKI, German and US experts further discussed the future of drug discovery and development and strengthened the bridge between drug research and industry.

Transdisciplinary cooperation in particular led us to great scientific successes in 2014 and 2015, which also attracted international atten-tion. Gulimila Shabuer, a doctoral researcher in the Department of Biomolecular Chemistry, for example, made a special discovery in collabo-


ration with Australian colleagues: The research group found a new strategy used by the the oxygen-sensitive potato pathogen Clostridium pu-niceum. The scientists detected a new group of active compounds, the clostrubins, which have antibiotic effects against other pathogens. The research group published the results in the re-nowned journal Science and was awarded the medac Research Prize for this.

In addition to about 330 other publications, numerous prizes and awards again attest to the quality and importance of our research. In particular, we congratulate Christian Hertweck on the DFG's Leibniz Prize. The most important award for scientists in Germany confirms Je-na's scientific reputation, which benefits Jena as a science location and the HKI in particular. The European Academy of Microbiology has elected Axel Brakhage as a new member, rec-ognizing his work in the field of diagnosis and therapy of life-threatening fungal infections. The German Society for Hygiene and Microbiology (DGHM) honored Axel Brakhage and Bernhard Hube jointly with the DGHM Main Award - one of the most important awards in the field of med-ical microbiology. In addition, Christine Skerka and Peter F. Zipfel received the Galenus von Pergamon Prize for their findings on the severe kidney disease Dense Deposit Disease. The molecule closthioamide discovered by Chris-tian Hertweck's team was chosen as Leibniz' Drug of the Year 2014. We continue to be very grateful to the medac AG. For many years, the company has donated the medac Research Prize, which is awarded to cooperative research projects at the HKI that are reflected in particu-larly high-ranking publications.

The work of the next generation of research-ers was also honored with renowned awards: Our doctoral researcher Tom Bretschneider was awarded the Leibniz Association's prize for

young scientists for his findings on the biosyn-thesis of the natural product rhizoxin. Qian Chen and Florian Kloß received awards for their out-standing doctoral theses by the Friedrich Schiller University Jena and the Beutenberg Campus.

Looking back, I would like to draw attention to the excellent result of the evaluation of the HKI. In its concluding statement, the Senate of the Leibniz Association certified the HKI as an international leader in the scientifically extreme-ly relevant fields of natural product and infection research. This very good evaluation result is mainly due to the great motivation and the colle-gial cooperation of all employees. And for that I thank the entire staff.

Axel Brakhage, Director HKI

CONTENTS INHALT

VorwortContents | InhaltDepartments | AbteilungenBiomolecular ChemistryInfection BiologyMicrobial Pathogenicity MechanismsMolecular and Applied MicrobiologyCell and Molecular BiologyResearch Groups | ForschungsgruppenApplied Systems BiologyFungal Septomics & National Reference Center for Invasive Fungal InfectionsMicrobial ImmunologySystems Biology and BioinformaticsIndependent Junior Research Groups | Unabhängige NachwuchsgruppenBiobricks of Microbial Natural Product SynthesesChemistry of Microbial Communication Chemical Biology of Microbe-Host InteractionsSecondary Metabolism of Predatory BacteriaCross-sectional Units | QuerschnittseinrichtungenBio Pilot PlantJMRC – Jena Microbial Resource CollectionILRS – International Leibniz Research SchoolAssociated Groups | Assoziierte GruppenInfections in Hematology / OncologyMicrobial Biochemistry and PhysiologyNetwork ModelingPharmaceutical Microbiology Facts and Figures | Zahlen, Daten, FaktenOrganization of the HKIInventions and Patents | Erfindungen und SchutzrechteExternal Funding | DrittmittelStaff | MitarbeiterPeer Reviewed Articles | OriginalarbeitenReviews, Monographs, Book Chapters | Übersichtsarbeiten, Monographien, SammelwerkeMemberships in Editorial Boards | Mitgliedschaften in Editorial BoardsLectures at the HKI | Kolloquien am HKIMeetings, Workshops, Symposia | Wissenschaftliche VeranstaltungenScientific Awards | Preise und AuszeichnungenCalls for Appointments | RufeGraduations | PromotionenBachelor / Master / Diploma Theses | Bachelor- / Master- / Diplomarbeiten

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DEPARTMENTBIOMOLECULAR CHEMISTRY

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MOST IMPORTANT RESULTS

Antibiotics from neglected bacteriaWith the rise and dissemination of multidrug-re-sistant pathogens, there is an urgent need for new antibiotics. To identify novel types of anti-microbial agents, the Department Biomolecular Chemistry focuses on neglected microbes such as anaerobic bacteria. These pioneering works led to the discovery of several novel leads, includ-ing closthioamide from a Clostridium species. Through systematic synthetic modifications of the closthioamide architecture crucial motifs of polythionamide antibiotics were identified. In collaboration with the group of Hans-Georg Sahl, University of Bonn, the molecular target of closthioamide was elucidated. It was found that closthioamide represents the first member of a novel class of bacterial DNA gyrase inhibi-tors. Mining the genomes of over 200 anaerobes revealed a huge potential for antimicrobial ribo-somally synthesized and post-translationally modified peptides (RiPP) in anaerobic bacteria (Letzel et al., 2014). Furthermore, we discovered unprecedented polyphenol antibiotics (clostru-bin A and B) in Clostridium species. These com-pounds play a key role in the post harvest plant disease potato soft rot. Clostrubins not only act as antibiotics against other microbial plant

pathogens, but also enable the anaerobic bacte-ria to survive an oxygen-rich plant environment (Pidot et al., 2014, Shabuer et al., 2015).

Metabolic profiling of endophytes from man-grove trees led to the discovery of the first an-tibacterial natural products (sulfadixiamycins A-C) with sulfanilamide and dapsone substruc-tures. Sulfa drugs (aromatic sulfonamides and diarylsulfones) are among the best known and most widely used antibacterial agents. In light of the relatively simple structures it is surpris-ing that such structural moieties are practically absent in naturally occurring molecules. Based on extensive in vivo experiments and retrobio-synthetic analysis we propose a biosynthetic scheme for sulfonamide and diarylsulfone for-mation involving an unprecedented enzyme- mediated sulfur dioxide capture (Baunach et al., 2015).

DEPARTMENT BIOMOLECULAR CHEMISTRY


Mechanisms of biosynthetic enzymesPolyketides typically result from head-to-tail con-densation of acyl thioesters to produce highly functionalized linear chains. The biosynthesis of the antimitotic agent rhizoxin, however, involves a polyketide synthase (PKS) module that intro-duces a δ-lactone chain branch through Michael addition of a malonyl extender to an α,β-unsatu-rated intermediate unit. To evaluate the scope of the branching module, polyketide mimics were synthesized and their biotransformation by the reconstituted PKS module was monitored in vitro. The impact of the type and configuration of the δ-substituents was probed and it was found that amino-substituted surrogates yield the cor-responding lactams. A carboxamide analogue was transformed into a glutarimide unit, which can be found in many natural products. Our findings illuminate the biosynthesis of glutarim-ide-bearing polyketides and also demonstrate the utility of this branching module for synthetic biology (Heine et al., 2014, Sundaram et al., 2015) Pathway engineeringReprogramming biosynthetic codes for multi-modular assembly lines has been considered to be a valuable synthetic biology approach to alter structures of peptides and complex polyketides. However, to date there has been no report on morphing a given modular polyketide

synthase into an assembly line that produces another genuine natural product. We have suc-ceeded in the first rational transformation of a modular PKS (for aureothin) to produce a com-plex polyketide (luteoreticulin) that was initially isolated from a different bacterium. A unique aspect of this study is that we used exclusive-ly genes from a single (aureothin) biosynthesis gene cluster to design the artificial luteoreticulin pathway. Beyond unveiling non-canonical PKS programming in the aur PKS, we showed that it is indeed possible to morph a given modular PKS to produce naturally occurring polyketides with different backbones (Sugimoto et al., 2014, Sugimoto et al., 2015). Through gene coexpres-sion and targeted gene manipulations, we also engineered the malleobactin pathway into an ornibactin assembly line. Such an evolution-ary-guided approach has been unprecedented for nonribosomal peptide synthetases. Further-more, we provided a compelling model for the evolution of virulence traits (Franke et al., 2014).

Fungal-bacterial InteractionsBased on our discovery of toxin-producing endo- fungal bacteria (Burkholderia rhizoxinica) living in the mycelium of the rice seedling blight fun-gus Rhizopus microsporus, the group strives to gain insight into the evolution and mediators of this unusual microbial alliance. We have now

IN A MULTIDISCIPLINARY APPROACH, THE DEPARTMENTBIOMOLECULAR CHEMISTRY INVESTIGATES THE STRUCTURAL

DIVERSITY, BIOSYNTHESIS AND FUNCTION OF BIOACTIVENATURAL PRODUCTS FROM MICROORGANISMS, WITH FOCUS ON

MEDICINALLY AND ECOLOGICALLY RELEVANT BIOSYSTEMS.

Christian Hertweck

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answered the question how bacteria invade the fungal cells. Genome mining for potential sym-biosis factors and functional analyses revealed that a type 2 secretion system (T2SS) of the bacterial endosymbiont is required for the for-mation of the endosymbiosis. The T2SS releas-es chitinolytic enzymes (chitinase, chitosanase) and chitin-binding proteins, of which at least chitinase is essential for bacteria to enter hy-phae. Our findings grant unprecedented insight into the fungal cell wall penetration and symbio-sis formation (Möbius et al., 2014).

Microbial virulence factorsThrough the combination of functional genetics, analytics and synthetic methods we have inves-

tigated several important microbial virulence factors. Malleobactins are siderophores em-ployed by human pathogenic bacteria belonging to the genus Burkholderia. We have elucidated the previously unknown structures of malleo-bactins and deciphered their biosynthesis and iron-binding capacities (Franke et al., 2014). We also found a novel pathway to bacterial polyynes (polyacetylenes). Mutational analysis of the caryoynencin (cay) biosynthesis gene cluster of the plant pathogen Burkholderia caryophylli re-vealed that novel desaturase/acetylenase genes mediate bacterial polyyne assembly. A fragile intermediate was chemically stabilized by an in situ click reaction (Ross et al., 2014).

Figure: (1) Model of processes involved in bacterial invasion. Chiti-nase as well as other effector proteins are secreted via a bacterial T2SS and induce a local dissolution of the fungal cell wall. This enables bacteria to enter and colonize the fungal cell and induce sporulation. (2) Course of infection of Burkholderia rhizoxinica (Br) to Rhizopus microsporus (Rm) observed by scanning cryo-electron microscopy. (A–D) Attachment/adherence of bacteria to fungal hyphae after 1 hr and (F–H) 20 hr of co-cultivation; (E–H) fusion of cell walls and the intrusion of bacterial cells into the fungal hyphae. Scale bars represent 5 µm. (3) Microscopic image of B. rhizoxinica (green) residing in the cytosol of R. microsporus. The endobac-terium is transmitted via fungal vegetative spores (upper right corner). Source: Moebius et al. eLife 2014;3:e03007. DOI: 10.7554/eLife.03007

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COLLABORATIONSDittmann, Elke University of Potsdam, Germany

Groll, Michael Technical University of Munich, Germany

Li, Ang Chinese Academy of Sciences, Shanghai, China

Pohnert, Georg Friedrich Schiller University Jena, Germany

Sahl, Hans-Georg University of Bonn, Germany

Schneider, Bernd Max Planck Institute for Chemical Ecology, Jena, Germany

SELECTED PUBLICATIONSShabuer G, Ishida K, Pidot SJ, Roth M, Dahse HM, Hertweck C (2015) Plant pathogenic anaerobic bacteria use aromatic polyketides to access aer-obic territory. Science 350, 670-674.

Sundaram S, Heine D, Hertweck C (2015) Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching. Nat Chem Biol 11, 949-951.

Baunach M, Ding L, Willing K, Hertweck C (2015) Bacterial synthesis of unusual sulfonamide and sulfone antibiotics by flavoenzyme-mediated sulfur dioxide capture. Angew Chem Int Ed 54, 13279-13283.

Moebius N, Uzüm Z, Dijksterhuis J, Lackner G, Hertweck C (2014) Active invasion of bacteria into living fungal cells. eLife, e03007.

Ross C, Scherlach K, Kloss F, Hertweck C (2014) The molecular basis of conjugated polyyne bio-synthesis in phytopathogenic bacteria. Angew Chem Int Ed 53, 7794-7798.

MAJOR THIRD PARTY FUNDINGDFG Collaborative Research Centre 1127 Chem-BioSys – Project B01 – Cryptic Mediators at the Bacterial-Fungal Interface: Mushroom Soft Rot Diseases as Infection Model

DFG Gottfried Wilhelm Leibniz Prize

DEPARTMENTINFECTION BIOLOGY

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New Achievements:The Department of Infection Biology and the group Immune Regulation work together to understand how the human immune system protects self surfaces and attacks non-self sur-faces. We want to understand (1) how microbial pathogens, in particular Candida albicans evade host innate immune recognition and (2) how defective immune regulators cause diseases, including the kidney diseases Hemolytic Uremic Syndrome (HUS) and CFHR Glomerulopathy, as well as degenerative neurological disorders like age related macular degeneration (AMD) and atherosclerosis.

Immune evasion of Candida albicans and microbial pathogensDuring millions of years of evolution the patho-genic yeast Candida albicans – similar to other pathogenic microbes – has learned to adapt to the human host, thereby controlling host im-mune recognition, immune attack and defense. We study how C. albicans controls host innate im-mune defense by identifying and characterizing immune evasion proteins. Many fungal immune evasion proteins are moonlighting proteins and act at different sites: At the fungal surface, they

attract human immune regulators. However, secreted into the surrounding medium they con-trol immune defense. In addition they modulate and often down regulate cellular inflammatory responses by binding to specific receptors on the surface of host immune cells. This immune camouflaging allows C. albicans, similar to other pathogens, to present itself to the host as ‘self-like’. Thereby the fungal proteins assist in inacti-vation of central host attack systems including complement and coagulation, which results in surviving this first line host immune attack and modulating the adaptive immune response. The functional characterization revealed common features of immune evasion which are shared by C. albicans and many other pathogenic mi-crobes.

Pra1, the pH regulated antigen of C. albicans, is such a multifunctional immune evasion protein that interacts with several human proteins. Pra1 expressed at the fungal surface binds human immune regulators, like Factor H and plasmino-gen. Secreted Pra1 binds C3 and C3 activation products and controls the innate immune sys-tem in the direct surrounding of the microbe. Recently we identified Pra1 as a fungal protease that directly cleaves and inactivates C3. In addi-tion, Pra1 also binds to receptors expressed on the surface of human immune cells, including CR3, CR4 and CD46. With this information, we are now further characterizing fungal proteins which bind to human immune cells via specific receptors and control host immune response to-ward this fungal pathogen. Human monocytes upon recognition of Candida albicans respond with an antifungal response. These cells release their DNA upon contact with Candida, and the released DNA traps the fungal invader and in ad-dition sets free antifungal compounds thereby attacking and killing the trapped fungal invader.

Genetic variations of human immuneregulators results in autoreactive diseasesCFHR Glomerulopathy is a severe kidney dis-

DEPARTMENT INFECTION BIOLOGY


Figure 1: Human monocytes upon contact with Candida al-

bicans release DNA to trap the pathogen.

Human monocytes respond to fungal invader by releasing DNA. Human monocytes with DNA stained in turquois upon contact with Candida albicans

(green fluorescence) burst and release their DNA to trap the

microbe. In addition the human immune cells release antifun-gal compounds that damage

the fungal invader. Insert: Candida trapped by released DNA strings is damaged by

antifungal proteins (EM image in collaboration with Martin

Westermann, Friedrich Schiller University Jena).

ease. The diagnosis is generally based on mor-phological changes in the glomerulus of the kidney, including thickening of the glomerular basement membrane and mesangial cell pro-liferation. Understanding the molecular causes of this kidney disease is central to generate less invasive or noninvasive diagnostic tools, to allow a better diagnosis and monitoring of appropriate treatment.

The various names used for overlapping mor-phological features already indicate a heteroge-neity of this kidney disorder. One major cause for C3 glomerulopathy are autoimmune factors, i.e. autoantibodies that bind to and stabilize the C3 convertase, the central complement enzyme. The further causes are genetic changes which present as gene mutations or copy number vari-

ations. The genes affected in glomerulopathy include Factor H, the central complement reg-ulator, C3, as a component of the convertase, CFHR1, CFHR2, CFHR3 and CFHR5. The latter represent emerging complement regulators.

Our group in collaboration with the clinicians from the nephrology unit from the university hospital in Erlangen has defined a new cause for C3 Glomerulopathy. A brother and a sister presented with MPGN II which was caused by deletion of a 25 kbp chromosomal segment in the CFHR gene cluster on chromosome 1q32. This brings a fragment of the human CFHR2 gene in close proximity to the CFHR5 gene and results in expression of a hybrid protein. The re-sulting CFHR2-CFHR5 hybrid protein acts as a complement activator, which stabilizes the C3

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convertase in fluid phase. This causes C3 con-sumption, resulting in continuous attack of the glomerular basement membrane leading to me-sangial cell damage and a loss of filtration.

The clinicians in Erlangen and our laboratory in Jena have started an intense exchange to under-stand the pathological principles of the hybrid protein in order to define the best options for treatment. Work in the laboratory has character-ized the hybrid protein as a complement activa-tor. Plasma addition aimed to remove the super activator was not successful. Next plasma ex-change was used in order to remove the defec-tive hybrid regulator. This treatment was effec-tive but already after 24 h the hybrid regulator was present again at previous levels. Currently we are evaluating which of the available comple-ment inhibitors can be used to dissociate the su-per stabilized C3 convertase and to disrupt the C3 Convertase::CFHR2-CFHR5 complex.

In parallel the physiological roles of CFHR2 and CFHR5 are analyzed. CFHR2 and CFHR5 bind C3b and CFHR2 as complement inhibitor blocks C3 convertase activity. CFHR5 is a surface bind-ing activator, which when bound to modified self surfaces, serves as an anchor for properdin, the known human complement activator.

WE ANALYZE HOW COMPLEMENT, THE CENTRAL IMMUNE SYSTEM,MAINTAINS HOMEOSTASIS AND HEALTH AND WHY

DISTURBANCES CAUSE INFECTIONS AND DISEASES. THIS APPROACHDEFINES PATHOGENIC PRINCIPLES OF INFECTIOUS MICROBES

LIKE CANDIDA ALBICANS, AS WELL AS OF NEUROLOGICALAND HUMAN KIDNEY DISEASES.

Peter F. Zipfel

Figure 2: The C3 Convertase (upper segment) forms the central hub of complement. This enzyme acts globally in the circulation but also locally in the kidney at surface. Defective regulation of this enzyme: The autoimmune factor C3 Nephritic Factor (left side) as well as a mutant CFHR5 protein (right) both bind to and stabilize the active enzyme. This results in increased activity, con-tinuous action and C3 consumption. The defective complement homeostasis enhances the attack of the glomerular basement membrane and of glomerular mesangial cells and thus leads to defective complement action. This results in kidney damage which is visualized as thickening of the glomerular basement membrane resulting in reduced and defective filtration.


COLLABORATIONSHabenicht, Andreas University Hospital Munich, Germany

Hammerschmidt, Sven University of Greifswald, Germany

Kraiczy, Peter University Hospital Frankfurt am Main, Germany

Riesbeck, Kristian Lund University, Sweden

Wiech, Thorsten University Hospital Hamburg-Eppendorf, Germany

Wiesener, Michael University of Erlangen, Germany

Thurman, Joshua University of Colorado Hospital, USA

SELECTED PUBLICATIONSHallström T, Uhde M, Singh B, Skerka C, Ries-beck K, Zipfel PF (2015) Pseudomonas aerugino-sa uses Dihydrolipoamide dehydrogenase (Lpd) to bind to the human terminal pathway regula-tors vitronectin and clusterin to inhibit termi-nal pathway complement attack. PLOS One 10, e0137630.

Zipfel PF, Skerka C, Chen Q, Wiech T, Rodríguez de Córdoba SR, Dragon Durey M, Fremeaux Bac-chi V, Goodship TH, Johnson S, Noris M, Picker-ing M, Nester CM, Smith RJ (2015) The role of complement in C3 glomerulopathy. Mol Immunol 67, 21-30.

Luo S, Hipler UC, Münzberg C, Skerka C, Zip-fel PF (2015) Sequence variations and protein

expression levels of the two immune evasion proteins Gpm1 and Pra1 influence virulence of clinical Candida albicans isolates. PLOS One 10, e0113192.

Chen Q, Wiesener M, Eberhardt HU, Hartmann A, Uzonyi B, Kirschfink M, Amann K, Büttner M, Goodship T, Hugo C, Skerka C, Zipfel PF (2014) Complement factor H related hybrid protein de-regulates complement in dense deposit disease. J Clin Invest 124, 145-155.

Mehta G, Ferreira VP, Skerka C, Zipfel PF, Banda NK (2014) New insights into disease-specific ab-sence of complement factor H related protein C in mouse models of spontaneous autoimmune diseases. Mol Immunol 62, 235-248.

MAJOR THIRD PARTY FUNDINGBMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC) – Candida albicans counteracts Dectin-mediated antifungal host response, MoPaRec

DFG Collaborative Research Centre /Transregio 124 FungiNet – Project C4 – Mechanisms of ad-hesion and modulation of human immune cells by Candida albicans

DFG Collaborative Research Centre /Transregio 124 FungiNet – Project C6 – Role of secreted Candida albicans proteins in immune evasion and pathogenicity

EU FP7 Health: EURenOMICS (European Con-sortium for High-Throughput Research in Rare Kidney Diseases)

DEPARTMENTMICROBIALPATHOGENICITYMECHANISMS

22


In the period 2014-2015, our research focused on three different main topics: (1) Experimental microevolution of Candida spp. during patho-genicity; (2) Interaction of Candida spp. with macrophages; and (3) Systematic phenotypic screening of C. glabrata mutant libraries in vitro and in vivo and large scale comparative analy-sis of infection models. We focused on C. albi-cans and C. glabrata as the two most important opportunistic pathogens among the Candida species.

(1) Host-pathogen interactions are constant battles: while pathogens adapt to the specific stresses and requirements inside their hosts, hosts are under selection for best defense against damage by these microorganisms. This evolutionary battle led to many astonishingly specific adaptations, from optimized microbial nutrient uptake systems to our adaptive im-munity. We are interested in the mechanisms responsible for the adaptation of C. albicans and C. glabrata during the infection process. It is known for both species that they exhibit phe-notypic and genotypic plasticity and can there-fore react to changing environments with new phenotypes. For example, microevolution has

clearly been demonstrated for the acquisition of antifungal drug resistance. We used serial pas-sage experiments to monitor the in vitro adap-tation of fungi to macrophages, key cells of the immune system. We used two models: a wild type strain of C. glabrata and a hyphal-deficient C. albicans strain which cannot escape from macrophages (as C. albicans normally does). In both cases we observed a striking change in the morphology of the strains after a series of co-culture passages. Usually, both strains grow as yeast cells, but during the microevolu-tion experiment they switched to a filamentous growth form. Interestingly, the ability to form fil-aments is a well characterized virulence trait in wild type C. albicans, which was recreated in the C. albicans evolved strain and newly gained in the C. glabrata evolved strain. We characterized the evolved strains in detail using in vitro and in vivo approaches to investigate the impact of this phenotypic alteration on the pathogenicity of the strains. To determine the underlying genetic

DEPARTMENTMICROBIAL PATHOGENICITY MECHANISMS


mechanisms which cause the phenotypic alter-ations, we used different molecular techniques like microarrays or DNA and RNA sequencing. We identified a single point mutation in the Me-diator complex to be responsible for the re-ap-pearance of hyphae formation in the previously non-filamentous C. albicans mutant. In C. glabra-ta, we found a chitin synthase mutation to be responsible for the morphological change.

(2) Phagocytes are key players of the innate immune system and constitute the first line of defense against fungal pathogens. Recognition of Candida cells by phagocytes leads to phago-cytosis and the activation of antimicrobial effec-tor functions to induce killing of the fungus. On the other hand, pathogenic Candida spp. are well adapted to their host and have developed mech-anisms to evade or counteract the anti-microbi-al activities of phagocytes. We have shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acid-ified late endosomal-stage phagosomes. We found that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lyso-somes and possess low phagosomal hydrolase activity. Inhibition of phagosome acidification occured independent of macrophage type, dif-ferentiation or activation status. We also ob-served that C. glabrata alkalinizes its extracellu-lar environment when growing on amino acids as the sole carbon source. By screening a C. gla-brata mutant library (below) we identified genes important for environmental alkalinization that were further tested for their impact on phago-some pH. Our results suggest that protein man-

nosylation may play a key role in modification of phagosomal properties by C. glabrata.

(3) As partner of the FunPath consortium, we have contributed to the construction of a large-scale C. glabrata deletion library consisting of 619 unique, individually bar-coded mutant strains, each lacking one specific gene, repre-senting almost 12 % of the genome. We used this library to systematically search for genes required for survival in phagocytes, in an alterna-tive infection model and in mice.

We identified several genes which are required to resist killing by macrophages. These genes are putatively involved in cell wall biosynthesis, calcium homeostasis, nutritional and stress response, protein glycosylation, or iron homeo-stasis. Our data imply that immune evasion is a key aspect of C. glabrata virulence and that in-creased immune recognition causes increased antifungal activities by macrophages. Further-more, stress resistance and efficient nutrient ac-quisition, in particular, iron uptake, are crucial for intraphagosomal survival of C. glabrata.

We also used the mutant library to systemati-cally compare the commonly used fruit fly with a mouse infection model for their similarities and degree of correlation upon infection. Using two indices, for fly survival time and for mouse fungal burden in specific organs, we show a good agreement between the models. We pro-vide a suitable predictive model for estimating the virulence potential of C. glabrata mutants in the mouse from fly survival data. We found

USING CELLULAR, MICROBIAL, MOLECULARAND BIOCHEMICAL METHODS WITH

CANDIDA ALBICANS AND C. GLABRATAAS MODEL ORGANISMS, THE GOAL OF OUR

RESEARCH IS TO UNDERSTAND HOW HUMANPATHOGENIC YEASTS CAUSE DISEASE.

Bernhard Hube

Figure 1: Visualising the matu-ration of C. glabrata-containing vacuoles. C. glabrata resides and replicates within macro-phages by modifying the mat-uration of their phagosomal compartment.

24

cell wall integrity mutants to be attenuated in flies, and mutants of a MAP kinase pathway to have defective virulence in flies and reduced rel-ative fitness in mice. In addition, mutants with strongly reduced in vitro growth generally, but not always, had reduced virulence in flies. Over-all, we demonstrated that surveying Drosophila survival after infection is a suitable model to predict the outcome of murine infections, espe-cially for severely attenuated C. glabrata mutants.

Pre-screening of mutants in an invertebrate Dro-sophila model can, thus, provide a good estimate of the probability of finding a strain with reduced microbial burden in the mouse host.

Figure 2: Laboratory evolution to elucidate the host-specific adaptations of pathogens. Both C. glabrata (top) and a nor-mally afilamentous C. albicans strain (bottom) gained the abil-ity to filament when exposed continuously to macrophages (middle).


COLLABORATIONSd‘Enfert, Christophe Institut Pasteur, Paris, France

Haas, Albert University of Bonn, Germany

Haynes, Ken University of Exeter, UK

Kuchler, Karl Medical University Vienna

Mansour, Michael Massachusetts General Hospital, Boston, USA

Quintin, Jessica Radboud University, Nijmegen, The Netherlands

Reiling, Norbert Research Center Borstel - Leibniz-Center for Medicine and Biosciences, Germany

Rupp, Steffen Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany

Schaller, Martin University of Tübingen, Germany

Vyas, Jatin Massachusetts General Hospital, Boston, USA

SELECTED PUBLICATIONSBrunke S, Quintin J, Kasper L, Jacobsen ID, Rich-ter ME, Hiller E, Schwarzmüller T, d‘Enfert C, Kuchler K, Rupp S, Hube B, Ferrandon D (2015) Of mice, flies - and men? Comparing fungal in-fection models for large-scale screening efforts. Dis Model Mech 8, 473-486.

Seider K, Gerwien F, Kasper L, Allert S, Brunke S, Jablonowski N, Schwarzmüller T, Barz D, Rupp S, Kuchler K, Hube B (2014) Immune evasion, stress resistance, and efficient nutrient acquisi-tion are crucial for intracellular survival of Can-dida glabrata within macrophages. Eukaryot Cell 13, 170-183.

Kasper L, Seider K, Gerwien F, Allert S, Brunke S, Schwarzmüller T, Ames L, Zubiria-Barrera C, Mansour MK, Becken U, Barz D, Vyas JM, Reiling N, Haas A, Haynes K, Kuchler K, Hube B (2014) Identification of Candida glabrata genes involved in pH modulation and modification of the phago-somal environment in macrophages. PLOS One 9, e96015.

Brunke S, Seider K, Fischer D, Jacobsen ID, Kasper L, Jablonowski N, Wartenberg A, Bader O, Enache-Angoulvant A, Schaller M, d’Enfert C, Hube B (2014) One small step for a yeast - Micro-evolution within macrophages renders Candida glabrata hypervirulent due to a single point muta-tion. PLOS Pathog 10, e1004478.

Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d‘Enfert C, Brun-ke S, Hube B (2014) Microevolution of Candida albicans in macrophages restores filamentation in a nonfilamentous mutant. PLOS Genet 10, e1004824.

MAJOR THIRD PARTY FUNDINGBMBF ERA-NET PathoGenoMics – Colonisation and the transition to pathogenic dissemination by Candida species: towards early diagnostic and therapeutic approaches, CandiCol

BMBF ERA-NET PathoGenoMics – Genomic Ap-proaches to Unravel the Molecular Mechanisms of Pathogenicity in the Human Fungal Pathogen Candida glabrata, FunPath

BMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care – Proj-ect D1.15 – In house professorship Molecular Mechanisms of Candida Sepsis and project D1.5

– Pathogen-host interaction during infection with Candida albicans and its progression to sepsis

DFG Collaborative Research Centre /Transregio 124 FungiNet – Project C1 - Molecular character-isation of Candida albicans mucosal colonisation, infection and translocation

DFG D-A-CH Lead Agency Action – Microevo-lution of pathogenic yeasts during interactions with the host immune system

DFG Priority Programme 1580 – Survival and proliferation of human pathogenic Candida spe-cies within phagocytes

DEPARTMENTMOLECULAR AND APPLIED MICROBIOLGY

28


Virulence of Aspergillus fumigatus and host-pathogen interactionsWe study the biology of the filamentous fungus A. fumigatus with particular focus on the identi-fication of virulence determinants and factors involved in host-pathogen interaction.

To search for fungal genes encoding putative vir-ulence determinants we initiated the generation of a genome-wide knock-out library of A. fumiga-tus in close collaboration with the groups of Mike Bromley and Jean-Paul Latgé. At the end of the reporting period, deletion mutants for 20 % of the ~ 10,000 genes were generated and stored at the Jena Microbial Resource Collection (JMRC).

Fungal signaling pathways, such as the cyclic AMP-dependent protein kinase A (PKA) cas-cade, are known to play important roles in patho-genicity. To search for downstrean targets of AMP/PKA in A. fumigatus, a transcriptomics ap-proach was applied, which led to the identifica-tion of FmpR, a fungal specific transcription fac-tor that regulates the biosynthesis of the novel secondary metabolite fumipyrrole. Interestingly, fumipyrrole proved to have immune modulatory functions.

In addition, interaction studies of spores with macrophages revealed that the fungal spore pigment dihydroxynaphthalene (DHN)-melanin inhibits phagolysosomal acidification and there-by allows the fungus to survive inside the host phagocytes. Confocal laser scanning microsco-py and proteome analysis were applied to char-acterize specific pathways important for this fungal immune evasion strategy.

Novel molecular mechanisms of iron sens-ing and homeostasis in filamentous fungiWe are interested in a better understanding of the molecular basis of fungal iron homeostasis, since adaptation to iron starvation is a crucial virulence determinant of Aspergillus fumigatus. In this fungus, upregulation of iron uptake mech-anisms and downregulation of iron-consuming pathways are under the control of the key iron regulator HapX via its interaction with the het-erotrimeric CCAAT-binding complex (CBC). In addition, we could show that HapX is essential for resistance to iron toxicity by activation of vac-uolar iron storage, which underlines that HapX senses the cellular iron status to coordinate the transcriptional remodeling of gene expression. This is mechanistically mediated by distinct cys-teine-rich protein domains, which are conserved in most HapX orthologs indicating conservation of this function in other fungal species. Further-more, we demonstrated that the CBC and HapX bind cooperatively to bipartite DNA motifs in a class of genes that are repressed by HapX:CBC during iron limitation in the model fungus Asper-gillus nidulans. This combinatorial binding mode requires protein-protein interaction between the N-terminal domain of the CBC subunit HapE and the N-terminal CBC-binding domain of HapX, as well as sequence-specific DNA-binding of both the CBC and HapX.

Microbial communication and natural productsMicroorganisms typically exist in multispecies communities in which they use secondary me-

DEPARTMENTMOLECULAR AND APPLIED MICROBIOLOGY


tabolites (SMs) as signal molecules to commu-nicate. The underlying mechanisms initiating SM formation are poorly understood. An excel-lent model system to elucidate such aspects is the interaction between Aspergillus nidulans and the bacteria Streptomyces rapamycinicus or S. iranensis. By reprogramming the fungal histone modification machinery the bacteria trigger the formation of orsellinic acid and its derivatives in the fungus.

To address the role of bacteria in gene clus-ter activation, we sequenced the genome of S.

iranensis. In addition, a protocol for the genera-tion of gene deletions in S. iranensis was estab-lished, allowing the study of biosynthetic genes potentially involved in bacterial-fungal interac-tion. Moreover, a random Tn5-based transposon mutant library of S. iranensis was constructed and screened for mutants lacking the ability to interact with A. nidulans. A single candidate gene was found and confirmed by a gene deletion. To elucidate the impact of chromatin modifica-tions in regulating SM gene cluster expression, we performed side-directed mutagenesis of amino acid residues which represent putative

targets of the histone acetyltransferase GcnE in the N-terminal tail of histone H3. In particu-lar lysine 14 affected product formation of sec-ondary metabolites including orsellinic acid. Hypoacetylation of both lysine 9 and 14 led to almost complete silencing of the orsellinic acid gene cluster. We further performed Chromatin Immunoprecipitation sequencing, which gave novel insight into the chromatin landscape of A. nidulans in regards to secondary metabolite gene clusters.

Stress- and immunoproteomicsWe investigate the dynamic changes of the pro-teome of human-pathogenic fungi exposed to adverse environmental conditions (e.g. during

THE DEPARTMENT FOCUSES ITS RESEARCH ON BOTH THEINFECTION BIOLOGY OF HUMAN-PATHOGENIC MOULDS AND FUNGAL

NATURAL PRODUCTS. THE AIM IS TO UNDERSTAND THE PATHOBIOLOGY OF ASPERGILLUS FUMIGATUS AND TO ELUCIDATE THE ROLE OF

NATURAL PRODUCTS AS MEDIATORS OF MICROBIAL COMMUNICATION.

Axel A. Brakhage

30

abiotic stress or in the course of infection). As tools, we use both 2D-gel electrophoresis and LC-MS/MS-based methods. For some time now, we have been exploring the question how A. fumig-atus adapts to low oxygen levels (hypoxia). Based on our transcriptome and proteome data we showed that mitochondrial respiration signifi-cantly contributes to the survival of A. fumigatus during hypoxic conditions. In addition, the fun-gus rapidly produces new proteins in response to low oxygen levels, including a previously unchar-acterized member of the sensor globin protein family we designated as fungoglobin. Deletion of the correponding gene confirmed its important role under extreme hypoxic conditions.

In collaboration with the group of Alexander Scheffold we characterized the human T-cell response to A. fumigatus protein antigens by using a newly developed sensitive enrichment technology. Intriguingly, in healthy humans As-pergillus-specific regulatory T cells (Tregs) are strongly expanded in comparison to conven-tional memory T-cells (Tmem). This suggests that the selective Tregs expansion represents an effective mechanism to prevent inappropri-ate immune activation.

COLLABORATIONSBowyer, Paul University of Manchester, UK

Bromley, Michael University of Manchester, UK

Haas, Hubertus University of Innsbruck, Austria

Latgé, Jean-Paul Institut Pasteur, Paris, France

Scheffold, Alexander Charité Universitätsmedizin Berlin, Germany

SELECTED PUBLICATIONSBacher P, Kniemeyer O, Schönbrunn A, Sawitz-ki B, Assenmacher M, Rietschel E, Steinbach A, Cornely OA, Brakhage AA, Thiel A, Scheffold A (2014) Antigen-specific expansion of human regulatory T cells as a major tolerance mecha-nism against mucosal fungi. Mucosal Immunol 7, 916-928.

Gsaller F, Hortschansky P, Beattie SR, Klammer V, Tuppatsch K, Lechner BE, Rietzschel N, Wer-ner ER, Vogan AA, Chung D, Mühlenhoff U, Kato M, Cramer RA, Brakhage AA, Haas H (2014) The Janus transcription factor HapX controls fungal adaptation to both iron starvation and iron ex-cess. EMBO J 33, 2261-2276.

Figure 1:Function of FmpR in A. fu-migatus. The gene encoding FmpR is part of a secondary metabolite cluster on chro-mosome VI. FmpR regulates transcription of all genes within this cluster. Activation results in biosynthesis of fumipyrrole. This novel fungal secondary metabolite potentially inhibits caspase-1 (Casp-1) of immune cells, thereby interferring with maturation of interleukin-1β (IL-1β).


Scharf DH, Habel A, Heinekamp T, Brakhage AA, Hertweck C (2014) Opposed effects of enzymat-ic gliotoxin N- and S-methylations. J Am Chem Soc 136, 11674-11679.

Macheleidt J, Scherlach K, Neuwirth T, Schmidt-Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Hertweck C, Heinekamp T, Brakhage AA (2015) Transcriptome analysis of cAMP-dependent protein kinase A regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus. Mol Microbiol 96, 148-162.

Valiante V, Monteiro MC, Martín J, Altwasser R, El Aouad N, González I, Kniemeyer O, Mellado E, Palomo S, de Pedro N, Pérez-Victoria I, Tormo JR, Vicente F, Reyes F, Genilloud O, Brakhage AA (2015) Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010). Antimicrob Agents Chemother 59, 5145-5153.

MAJOR THIRD PARTY FUNDINGDFG Collaborative Research Centre 1127 Chem-BioSys – Project B02 – Mechanisms of Bacte-ria-triggered Activation of Fungal Silent Gene Clusters and Impact of Produced Compounds on Microorganisms

DFG Collaborative Research Centre / Transregio 124 FungiNet – Project A1 – Cross-talk of Asper-gillus fumigatus with neutrophilic granulocytes

DFG D-A-CH Lead Agency Action – Novel molec-ular mechanisms of iron sensing and homeosta-sis in filamentous fungi

DFG Excellence Graduate School Jena School of Microbial Communication

BMBF ERA-NET PathoGenoMics – Biomarkers for prevention, diagnosis and response to thera-py of invasive aspergillosis, AspBIOmics

BMBF ERA-NET PathoGenoMics – Human fun-gal pathogens under oxygen stress: adaptive mechanisms to hypoxia and reactive oxygen species and their consequences for host inter-action and therapy, OXYstress

BMBF Project EXASENS – POC-sensor platform for chronic inflammatory respiratory diseases

BMBF Zwanzig20 – Partnerschaft für Inno-vation Consortium InfectControl 2020 – New anti-infection strategies – Projects FINAR and Transectoral Research Platform, TFP

EU FP7 Marie Curie Initial Training Network (ITN) QuantFung – Discovery of Streptomycetes in-duced fungal secondary metabolite formation

Figure 2: Scheme of the regu-latory mechanism mediating both adaptation to iron starva-tion and iron toxicity by the iron sensor HapX via combinatorial bipartite motif recognition with the heterotrimeric CBC.

DEPARTMENTCELL ANDMOLECULAR BIOLOGY

34


Microbiome-host interactionsThese studies concerned the taxonomic and functional characterisation of the microbial gut communities in economically and alimentary relevant marine organisms in Indonesian coast-al areas under pollutant and non-pollutant con-ditions. The microbiome included bacterial, fun-gal, protistan, and viral species, many of which pose threats to human and animal health, and/or impact sustainability of food production. By employing a culture-independent metagenomic approach, we generated taxonomic profiles and snapshots of metagenome gene content for fe-cal samples.

Aspergillus fumigatus infection and its role during host cell apoptosis Using hyperspectral imaging we showed that melanin of A. fumigatus conidia has the ability to interfere with the apoptosis process in human monocytes by enabeling the apoptotic cells to recover from mitochondrial acidification and thus to continue their life cycle.

Chlamydia psittaci: An underestimated zoonotic pathogenChlamydia (C.) psittaci, the causative agent of ornithosis, is an obligate intracellular pathogen with a unique developmental cycle and a high potential for zoonotic transmission. A key step in understanding the mechanisms of chlamydial pathogenesis is the identification of C. psittaci infection-associated protein antigens. Using the immunoscreening approach in vivo Induced An-tigen Technology (IVIAT), experiments with sera of infected calves revealed 19 immunogenic proteins, which are expressed during infection. They are involved in important pathways of the host cell.

C. psittaci uses dynein motor proteins for opti-mal early development. Chlamydial proteins that mediate this process are unknown. Two-hybrid screening with the C. psittaci inclusion protein IncB as bait against a HeLa Yeast Two-hybrid (YTH) library revealed that the host protein Snapin interacts with both IncB and dynein in vi-tro and in vivo. We propose that Snapin connects chlamydial inclusions with the microtubule net-work.

Quantification of experimental arthritis with PET/CT Imaging To assess pathological changes of the bones in the course of arthritic diseases, experimen-tal models are frequently used. In this project we focused on the quantitative evaluation of pathological bone metabolism and bone ero-sion caused by glucose-6-phosphate isomerase (G6PI)-induced arthritis in mice. Therefore we

DEPARTMENTCELL AND MOLECULAR BIOLOGY


RESEARCH IN THE DEPARTMENT OF CELL AND MOLECULAR BIOLOGYIS DEVOTED TO THE FLOW OF MOLECULAR INFORMATION DURING

HOST-PATHOGEN INTERACTIONS. WITHIN THIS FRAMEWORK, WE AIM AT THE ELUCIDATION OF HOW INFECTIONS PROCEED IN LIVING ORGANISMS

AND HOW INFECTED ORGANS REACT ON A MOLECULAR LEVEL.

Hans Peter Saluz

Figure 1: In vitro Induced Antigen Technology (IVIAT) applied to obligate intracellular bacteria.

36

performed longitudinal, in vivo positron emission tomography/computed tomography (PET/CT) imaging with the bone seeking tracer [18F]-flu-oride. We found that this tracer is eminently suited to quantify pathologically increased bone metabolism throughout the course of arthritis. Additionally, high-resolution CT scans of the an-imals hind paws were used to establish a sensi-tive quantification technique that is able to deter-mine the bone damage caused by G6PI-induced arthritis. For this purpose, we calculate the sur-face roughness of bony and cartilage structures which increases with progressing bone erosion. In this context we found that bone erosion occurs on a certain spatial scale for endosteal as well as periosteal sites of the bones. This combination of functional and anatomical imaging makes an important contribution to reduce the number of animals needed in preclinical research, while giving new insights into arthritic processes and opportunities to refine drug evaluation.

Real-time detection of microbial surface communitiesIn this project, UV LEDs are used as compact and economic light sources for fluorescence excitation. In close collaboration with industry and research partners a functional model of a portable sensor has been developed. As proof of concept the detection of microbial surface contaminations has been demonstrated, where-by the fluorescence spectra of several microbi-al fluorophores serve as fingerprints. The main field of application concerns food and beverage industry. Rapid microbial detection enables real- time hygiene monitoring leading to increased food safety. Within the framework of “Advanced UV for Life” – a large technology-driven nation-al research consortium funded by the BMBF – both, differentiation of microbial species and an increasing detection limit, are central tasks.

The primary transcriptome of infectious and non-infectious C. psittaci, C. abortus and Waddlia chondrophila particlesAll members of the phylum Chlamydiae share a characteristic biphasic developmental cy-cle where infectious, extra-cellular elementary bodies (EBs) and non-infectious reticulate bod-ies (RBs) alternate. For many studies involving Chlamydiae it is crucial to apply highly purified EB and RB-fractions. For this reason we devel-oped a novel purification procedure using iodix-

anol for density gradient preparation. Iodixanol is repeatedly reported to be superior to other gradient media and was applied for purification of proteins, viruses and organelles. Our purifica-tion procedure yielded in pure chlamydial parti-cles and demonstrated the performance of this approach by TEM, reinfection assays and qual-ity of isolated RNA. With our protocol in hand we purified RBs and EBs of zoonotic C. abortus and C. psittaci and potentially zoonotic Waddlia chondrophila. We isolated RNA, enriched prima-ry transcripts using a 5‘-phosphate-dependent- exonuclease and prepared cDNA libraries for RNA sequencing. With the RNA-Seq data we are now able to analyze the transcriptomes of EBs and RBs in zoonotic chlamydial species.

COLLABORATIONSMonajembashi, Shamci Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany

Palm, Harry University of Rostock, Germany

Sachse, Konrad Friedrich-Loeffler-Institut Jena, Germany

PURION GmbH, Zella-Mehlis, Germany

SELECTED PUBLICATIONSKästner J, Saluz HP, Hänel F (2015) Identifica-tion of in vivo-induced bacterial protein antigens during calf infection with Chlamydia psittaci. Int J Med Microbiol 305, 310-321.

Hänel F, Saluz HP (2016) Chlamydiacae: Poly-morphic membrane proteins make the differ-ence. Virulence. 7, 3-4.

Böcker S, Heurich A, Franke C, Monajembashi S, Sachse K, Saluz HP, Hänel F (2014) Chlamydia psittaci inclusion membrane protein IncB associ-ates with host protein Snapin. Int J Med Microbiol 304, 542-553.

Amin S, Thywissen A, Heinekamp T, Saluz HP, Brakhage AA (2014) Melanin dependent survival of Aspergillus fumigatus conidia in lung epithelial cells. Int J Med Microbiol 304, 626-636.

Irmler IM, Gebhardt P, Hoffmann B, Opfermann T, Figge MT, Saluz HP, Kamradt T (2014) 18 F-Flu-oride positron emission tomography/computed


tomography for noninvasive in vivo quantifica-tion of pathophysiological bone metabolism in experimental murine arthritis. Arthritis Res Ther 16, R155.

MAJOR THIRD PARTY FUNDINGBMBF German Research Platform for Zoonoses – Zoonotic chlamydiae – Models of chronic and persistent infections in humans and animals

BMWi Project – Optisches Detektionssystem für den Sofortnachweis von Mikroorganismen in Lebensmittelproduktionsmaschinen, Opti-MikroL

BMBF Zwanzig20 – Partnerschaft für Innova-tion Consortium Advanced UV for Life – Project Stationary fluorescence-based germ detection on surfaces

Figure 2: (A) [18F]-fluoride PET and CT image fusion at day 14 after immunization with G6PI shows increased tracer uptake in ankles, knees and tarsocrural joint regions. (B) At day 10 after immunization a reconstructed surface mesh reveals smooth (blue) and rough (green) regions as well as first lesions in the cortical substance of a hind paw, which are also visible in the corre-sponding cross-sectional CT slice (arrow).

RESEARCH GROUPAPPLIED SYSTEMS BIOLOGY

40


In the research group Applied Systems Biology, we performed a number of studies in close col-laboration with experimental scientists at the Hans Knöll Institute and beyond. In this context, algorithms were developed that enable (1) auto-mated image processing and (2) computer sim-ulations of virtual infection models.

A pipeline for the analysis of endpoint imaging experiments was developed for confrontation assays between alveolar macrophages and fun-gal cells, such as spores of Aspergillus fumigatus or Lichtheimia corymbifera. This enabled quanti-

tative investigation of phagocytosis by compar-ing different mutants and medium conditions. The fully automated analysis was also applied in the context of identifying the antiphagocytic trypacidin gene cluster in A. fumigatus. It could be shown that conidium-bound trypacidin has a protective function against phagocytes both in the environment and during the infection pro-cess.

A segmentation method was newly developed that allows tracking of unstained cells in live cell imaging videos. The analysis was extended to phagocytosis assays revealing that neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Moreover, it was observed and quantified that human neutrophils dump C. glabrata after in-tracellular killing in 15 % of all observed killing events. Whether this is a strategy to provide other immune cells with the opportunity to take up dead fungal cells and present antigens for induction of adaptive responses remains to be investigated.

In two studies, the image-based systems biology approach also involved computer simulations. For example, fluorescence microscopy with dif-ferential staining was applied to follow epithelial invasion by hyphae of C. albicans in a time-series of images. A state-based model to simulate this dynamical process revealed that epithelial inva-sion outcompetes hypha development, i.e. the initiation of hyphae formation represents an ulti-mate commitment to invasive growth. In vivo the yeast to hypha transition must be under negative regulation to avoid this commensal-to-pathogen transition. Similarly, but in a completely different context, Monte Carlo simulations were used to quantify cell co-localization in murine bone mar-row from images gained by confocal laser scan-ning microscopy.

RESEARCH GROUPAPPLIED SYSTEMS BIOLOGY


THE INVESTIGATION OF DYNAMICAL, FUNCTIONAL AND MORPHOLOGICAL ASPECTS OF INTERACTIONS BETWEEN FUNGI AND THE HUMAN HOST IS

PERFORMED BY IMAGE-BASED SYSTEMS BIOLOGY. THIS MODERN APPROACH COMBINES THE AUTOMATED PROCESSING AND QUANTIFICATION OF IMAGES

WITH COMPUTER SIMULATIONS OF MATHEMATICAL MODELS.

Marc Thilo Figge

A number of systems exist that are highly rel-evant for infection research but where in vivo imaging is technically not possible today, e.g. al-veoli of the lung and whole blood. Predictive sim-ulations of virtual infection models have been used to quantify innate effector mechanisms and C. albicans immune escape in human blood. This was achieved by a bottom-up approach combining state-based and agent-based mod-eling. Similarly, early A. fumigatus infection was simulated by an agent-based model of human alveoli. This led to the prediction of a chemotac-tic signal whose properties were subsequently deciphered to support its experimental identifi-cation in the future.

COLLABORATIONSHauser, Anja German Rheumatism Research Centre, Berlin, Germany

Lücke, Jörg University of Oldenburg, Germany

GILUPI GmbH, Potsdam, Germany

42

automated image

processing

quantitative characterization

predictive computer simulations

generation of testable hypotheses

Image-based Systems Biology

SELECTED PUBLICATIONSBrandes S, Mokhtari Z, Essig F, Hünniger K, Kur-zai O, Figge MT (2015) Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neu-trophils. Med Image Anal 20, 34-51.

Kraibooj K*, Schoeler H*, Svensson CM, Brak-hage AA, Figge MT (2015) Automated quan-tification of the phagocytosis of Aspergillus fumigatus conidia by a novel image analysis algorithm. Front Microbiol 6, 549. * authors con-tributed equally.

Lehnert T*, Timme S*, Pollmächer J, Hünniger K, Kurzai O, Figge MT (2015) Bottom-up model-ing approach for the quantitative estimation of parameters in pathogen-host interactions. Front Microbiol 6, 608, * authors contributed equally.

Mech F, Wilson D, Lehnert T, Hube B, Figge MT (2014) Epithelial invasion outcompetes hypha development during Candida albicans infection as revealed by an image-based systems biology approach. Cytometry A 85, 126-139.

Svensson CM, Krusekopf S, Lücke J, Figge MT (2014) Automated detection of circulating tumor cells with naive Bayesian classifiers. Cytometry A 85, 501-511.

Image-based Systems Biology: Microscopy images are auto-matically processed by algo-rithms and biological procsses are quantified. The obtained quantitative data form the basis for mathematical models and computer simulations of the biological process to gen-erate hypotheses that can be tested in further experiments.

MAJOR THIRD PARTY FUNDINGBMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC) – Quantification of Innate Immune Mechanisms in Whole Blood Infection Assays, QUANTIM

DFG Collaborative Research Centre / Transregio 124 FungiNet – Project B4 – Image data analy-sis and agentbased modeling of the spatiotem-poral interaction between immune cells and hu-manpathogenic fungi

DFG Joint Intravital Microscopy and Imaging platform, JIMI - a network for intravital micros-copy: dedicated project supervision from cell imaging to cell tracking in living organisms

Leibniz Association Leibniz ScienceCampus InfectoOptics – Project Whole Blood Imaging, BLOODi

Free State of Thuringia – Microfluidic Technolo-gy for High-Throughput Screening for novel anti-biotics produced by micro-organisms, DropCode

RESEARCH GROUPFUNGAL SEPTOMICS & NATIONALREFERENCE CENTER FOR INVASIVE FUNGAL INFECTIONS

46


Worldwide, a steadily growing number of pa-tients are at risk for invasive fungal infections (IFI). Pathogenic yeasts in the genus Candida and filamentous Aspergillus spp. are the most important causes of IFI in Europe, whereas Cryp-tococcus neoformans plays a major role in Afri-ca. However, an increasing variety of rare fungal pathogens are identified in IFI, especially in se-verely immune-compromised patients. In our Fungal Septomics team, we investigate the in-fection biology of IFI with a focus on the interac-tion between fungal pathogens and the human host. Within the National Reference Center for Invasive Fungal Infections (NRZMyk) we direct-ly apply our findings and expertise in the clinical setting by providing diagnostic tests beyond the scope of routine diagnostic labs.

Our work addresses aspects of fungal virulence biology that determine interaction with the hu-man host as well as the host response during IFI in three major research areas:

Adaptation of fungal pathogensto host nichesThe ability of fungal pathogens to adapt to their host niches is critical for establishing invasive

infection. A major example is morphogenesis of C. albicans which is closely related to tissue in-vasion and innate immune activation. We could show that the quorum-sensing molecule farne-sol, which regulates morphogenesis in C. albi-cans, can act as a virulence factor by modulating cellular adaptive responses critical for protective immunity. In ongoing work we analyze regula-tory cascades governing morphogenesis in C. albicans with a focus on CO2 induced signaling.

Innate immune recognition offungal pathogens We have established a range of infection models for primary human immune cells including neu-trophils, monocytes, dendritic cells and natural killer (NK-) cells. Of particular importance was the establishment of a whole blood infection model that is now broadly used also by other

RESEARCH GROUP FUNGAL SEPTOMICS &NATIONAL REFERENCE CENTER FORINVASIVE FUNGAL INFECTIONS


COMBINING BASIC RESEARCH WITH CLINICALAPPLICATION WE AIM TO BROADEN OUR

KNOWLEDGE ON SYSTEMIC FUNGAL INFECTIONS AND IMPROVE THEIR CLINICAL MANAGEMENT.

Oliver Kurzai

groups at the HKI. Importantly, in collaboration with the research group Applied Systems Biolo-gy a virtual infection model has been developed to quantify host-pathogen interaction dynam-ics in silico based on experimental data. Using these models, we have characterized early im-mune activation by C. albicans, C. glabrata and A. fumigatus and the role of NK-cells in IFI.

Genetic risk factors for fungalinfectionTo analyze inter-individual differences in human susceptibility to IFI we correlate genetic poly-morphisms with functional consequences in the immune response to fungal pathogens. A major effort is the coordination of the AspIRS international multi-centre study on genetic risk factors for invasive aspergillosis. In cooperation with several European groups we could identify a polymorphism in pentraxin 3 that confers in-creased risk for invasive aspergillosis after allo-geneic stem cell transplantation.

Clinical application of our work has been ex-panded with the appointment as German Na-tional Reference Center for Invasive Fungal Infections (NRZMyk) in 2014 by the Federal Min-istry of Health and the Robert Koch-Institute. Since then, the NRZMyk has developed into a central contact point for diagnostics and man-agement of invasive fungal infections, handling more than 300 clinical samples from more than

70 sites in Germany each year. Major tasks in-clude identification of rare fungi using molecular reference methods. Beside identification of clin-ical isolates (more than 26 genera in 2015), mo-lecular detection of fungal pathogens in tissue samples is a major part of the NRZMyk work. For this, a portfolio of species- or group-specific PCRs as well as universal fungal PCRs has been established. Susceptibility testing is performed using EUCAST microdilution protocols as well as molecular detection of resistance confirming mutations. All identified strains are stored in the stock collection of the NRZMyk at the Jena Mi-crobial Resource Collection JMRC and isolates from the collection can be provided on request to diagnostic institutions. In addition to offering reference diagnostics, the NRZMyk expanded its research projects for development and improve-ment of diagnostic and therapeutic tools con-siderably in 2015. In a DFG funded project the taxonomic structure of Mucoraceae is revisited. Together with partners from Halle, Leipzig and Dresden the development of azole resistance in Aspergillus fumigatus in the environment is an-alyzed in the BMBF funded InfectControl 2020 project FINAR coordinated by the NRZMyk. The NRZMyk maintains close contacts to other Euro-pean mycological reference centers as well as to relevant committees of ESCMID and ISHAM. Oli-ver Kurzai acts as German representative for the Antifungal Susceptibility Testing Subcommittee (AFST) of the EUCAST and is a member of the

Figure 1: Histopathology showing invasive pulmonary fungal infection in an immuno-compromised patient. Using molecular tools, Aspergillus flavus could be identified as the causative agent.

48

National Antibiotics Sensitivity Test Committee (NAK) involved in standardizing mycological susceptibility testing procedures. The NRZMyk has been appointed as EUCAST AFST network laboratory for yeasts and moulds.

COLLABORATIONSBrunkhorst, Frank AlertsNet 2.0, Jena, Germany

Carvalho, Agostinho University of Minho, Guimarães, Portugal

Cornely, Oliver FungiScope, Cologne, Germany

Deising, Holger University of Halle, Germany

Einsele, Hermann Julius Maximilians University Würzburg, Germany

Geerling, Gerd University Hospital Düsseldorf

Löffler, Jürgen Julius Maximilians University Würzburg, Germany

Romani, Luigina University of Perugia, Italy

Figure 2: Human neutrophils release intracellularly killed Candida glabrata. GFP-ex-pressing C. glabrata were con-fronted with primary human neutrophils in the presence of propidium iodide (PI). PI selectively stains dead cells due to the lack of an intact cell membrane. Therefore, dead cells can be identified by red fluorescence.


Roth, Mathias University Hospital Düsseldorf, Germany

Schmidt, Volker University of Leipzig, Germany

Schumacher, Johannes University of Bonn, Germany

BioType GmbH, Dresden, Germany

Inflarx GmbH, Jena, Germany

SELECTED PUBLICATIONSHünniger K, Lehnert T, Bieber K, Martin R, Fig-ge MT, Kurzai O (2014) A virtual infection model quantifies innate effector mechanisms and Can-dida albicans immune escape in human blood. PLOS Comput Biol 10, e1003479.

Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, Löffler J, Maertens JA, Bell AS, Infor-zato A, Barbati E, Almeida B, Santos e Sousa P, Barbui A, Potenza L, Caira M, Rodrigues F, Salva-tori G, Pagano L, Luppi M, Mantovani A, Velardi A, Romani L, Carvalho A (2014) Genetic PTX3 deficiency and aspergillosis in stem-cell trans-plantation. N Engl J Med 370, 421-432.

Voigt J, Hünniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, Löffler J, Kurzai O (2014) Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis 209, 616-626.

Duggan S, Essig F, Hünniger K, Mokhtari Z, Bau-er L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O (2015) Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17(9), 1259-1276.

Leonhardt I, Spielberg S, Weber M, Albrecht-Eck-ardt D, Bläss M, Claus R, Barz D, Scherlach K, Hertweck C, Löffler J, Hünniger K, Kurzai O (2015) The fungal quorum-sensing molecule farnesol activates innate immune cells but sup-presses cellular adaptive immunity. mBio 6(2), e00143.

MAJOR THIRD PARTY FUNDINGBMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC) – Quantification of Innate Immune Mechanisms in Whole Blood Infection Assays, QUANTIM

BMBF Zwanzig20 – Partnerschaft für Innova-tion Consortium InfectControl 2020 – New an-ti-infection strategies – Scientific Administra-tion and Project FINAR

BMG and RKI – National Reference Center for Invasive Fungal Infection, NRZMyk

DFG Collaborative Research Centre /Transregio 124 FungiNet – Project C3 – Intrinsic modula-tion of neutrophil antifungal activity against Can-dida albicans

DFG Project CO2 Adaption in Candida glabrata and its role in host-pathogen interaction

DFG Project Polyphasic taxonomic revision of Mucoraceae

RESEARCH GROUPMICROBIAL IMMUNOLOGY

52


Murine models are essential to study both the commensal phase of Candida and the pathogen-esis of candidiasis. So far, however, the analysis of disease progression and therapy efficacy was based on the determination of renal fungal bur-den post mortem. To allow longitudinal studies in vivo, we developed a real-time non-invasive imaging approach based on bioluminescent C. albicans reporter strains. This allowed the in vivo monitoring of infection and determination of fun-gal burden in living animals. Using this approach we discovered that under clinically efficient an-tifungal treatment, C. albicans is able to persist in the gall bladder. Fungi were secreted with bile

and detected in the faeces, implicating the gall bladder as a reservoir and possibly explaining why in some patients systemic Candida infec-tions recur after initially successful treatment.

We also used in vivo imaging to investigate colonization of the gastrointestinal tract by C. albicans and found that while faecal burden remained relatively stable over the course of colonization, in vivo imaging revealed dynamic foci of increased signal intensity. Whether these foci indicate sites of increased fungal density or invasion is currently under investigation. One potential factor contributing to translocation from the gut is mesenteric ischemia, leading to local hypoxia that can impair the gut barrier. This hypothesis was investigated in vitro; sur-prisingly, hypoxia did enhance adhesion but not invasion and damage, whereas invasion, host cell damage and translocation increase during reperfusion. In ongoing experiments we aim to determine the underlying mechanisms.

Another research focus is the pathogenesis of disseminated candidiasis. In mice, C. albicans infects almost all organs after intravenous ap-plication; however, while C. albicans is gradual-ly cleared from liver and spleen, infection pro-gresses in the kidneys. To better understand the mechanisms of this organ-specific outcome, we performed gene expression profiling of the fungus and the host tissue. The results indicate

RESEARCH GROUP MICROBIAL IMMUNOLOGY


WE INVESTIGATE THE INTERACTIONS BETWEEN CANDIDA ANDTHE HOST, AIMING AT A BETTER UNDERSTANDING OF THE INTERACTIONS

THAT LEAD TO COLONIZATION, PATHOPHYSIOLOGICAL ALTERATIONSAND TO THE DEVELOPMENT OF CLINICAL DISEASE.

Ilse D. Jacobsen

a delayed immune response accompanied by unhindered growth of the fungus in the kidneys. In contrast, proinflammatory responses oc-curred early in the liver and a fungal response suggesting interaction with phagocytes which likely mediates fungal control in the liver. Nota-bly, hypha-associated genes were upregulated in the absence of visible filamentation in the liver, indicating an uncoupling of gene expres-sion and morphology. As morphogenesis is a key virulence attribute of C. albicans, we aimed to elucidate the exact role of EED1, a gene re-quired for hyphal maintenance. We discovered that EED1 reduces sensitivity to farnesol, a quorum sensing molecule that suppresses fila-mentation. In addition, EED1 regulates farnesol production and the hyphal maintenance-defect in the eed1Δ mutant strain is at least partially linked to farnesol.

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Bioluminescence in vivo im-aging allows visualisation of Candida albicans infection in living mice.


COLLABORATIONSBauer, Michael University Hospital Jena, Germany

Beilhack, Andreas University Hospital Würzburg, Germany

SELECTED PUBLICATIONSJacobsen ID, Lüttich A, Kurzai O, Hube B, Brock M (2014) In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifun-gal therapy. J Antimicrob Chemother 69, 2785-2796.

Hebecker B, Naglik JR, Hube B, Jacobsen ID (2014) Pathogenicity mechanisms and host re-sponse during oral Candida albicans infections. Expert Rev Anti Infect Ther 12, 867-879.

Quintin J, Voigt J, van der Voort R, Jacobsen ID, Verschueren I, Hube B, Giamarellos-Bour-boulis EJ, van der Meer JW, Joosten LA, Kurzai O, Netea MG (2014) Differential role of NK cells against Candida albicans infection in immuno-competent or immunocompromised mice. Eur J Immunol 44, 2405-2414.

Brunke S, Quintin J, Kasper L, Jacobsen ID, Rich-ter ME, Hiller E, Schwarzmüller T, d‘Enfert C, Kuchler K, Rupp S, Hube B, Ferrandon D (2015) Of mice, flies - and men? Comparing fungal in-fection models for large-scale screening efforts. Dis Model Mech 8, 473-486.

Polke M, Hube B, Jacobsen ID (2015) Candida survival strategies. Adv Appl Microbiol 91, 139-235.

MAJOR THIRD PARTY FUNDINGBMBF InfectoGnostics Research Campus – In-novative Diagnostik für Pneumonien bei Immun-suppression, IDES

BMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC)

– Interactions between Candida albicans and bac-teria, CanBac

DFG Collaborative Research Centre / Transregio 124 FungiNet – Project C5 – Gastrointestinal colonisation and mechanisms of translocation of Candida albicans through gut mucosa

RESEARCH GROUPSYSTEMS BIOLOGY ANDBIOINFORMATICS

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We computationally analyzed gene expression data of fungi producing secondary metabolites as well as of the pathogenic fungi Candida albi-cans and Aspergillus fumigatus and their interac-tion with the human immune system.

We developed and host a data warehouse for the management of heterogeneous large-scale experimental data and software tools for data pre-processing, data mining to discover bio-markers and modeling for prediction of experi-mentally testable hypotheses. Such hypotheses are molecular interactions between host and pathogen, or between transcription factors and their target genes within the host or the patho-gen, or the fungus that produces a natural prod-uct of interest.

For instance, we identified the S100 calci-um-binding protein B (S100B) as a potential new biomarker for the diagnosis of Invasive Aspergil-losis and we demonstrated the influence of the Krüppel-like factor 4 (KLF4) on the interleukine-6 expression in human human dendritic cells after in vitro stimulation with A. fumigatus and C. albi-cans.

We developed the first genome-wide gene regu-latory network (GRN) model for A. fumigatus and are updating our model for C. albicans.

We published a detailed RNA-Seq-based analy-sis of the transcriptomic landscape of C. glabrata in nutrient-rich media, as well as under nitrosa-tive stress and during pH shift. Using RNA-Seq data together with state-of-the-art gene pre-diction tools, we refined the annotation of the C. glabrata genome and predicted 49 novel pro-tein-coding genes. We developed FungiFun, a user-friendly web-tool for functional enrichment analysis of fungal genes and proteins. We further developed and tested modeling of pathogen-host-interaction based on dual RNA-Seq data with the aim to pre-dict molecular inter-species interactions. There-fore, we extended NetGenerator, a network infer-ence tool that predicts gene regulatory networks from gene expression time series data.

A systems biology approach, based on compre-hensive transcriptome data sets and mathemat-ical modeling, was employed to infer a GRN of A. fumigatus and identify key interactions during adaptation to antimycotical caspofungin stress.

RESEARCH GROUPSYSTEMS BIOLOGY AND BIOINFORMATICS


Mathematical modeling and experimental vali- dations confirmed a cross talk occurring be-tween the cell-wall integrity and the high osmo-larity-glycerol signaling pathways.

Futhermore, we inferred a GRN to hypothetically explain the biphasic pattern of the transcription-al host response associated with coevolution of hemagglutinin quasispecies of influenza A virus.We annotated and published the draft genome sequence of various fungi.

We developed the software CASSIS (Cluster Assignment by Islands of Sites), a method for Secondary Metabolite (SM) Synthesis cluster prediction in eukaryotic genomes, and SMIPS (SM by InterProScan), a tool for genome-wide detection of SM key enzymes.

COLLABORATIONSEnglert, Christoph Leibniz Institute on Aging - Fritz Lipmann Insti-tute (FLI), Jena, Germany

Gebhardt, Rolf University of Leipzig, Germany

Löffler, Jürgen Julius Maximilians University Würzburg, Germany

Platzer, Matthias Leibniz Institute on Aging - Fritz Lipmann Insti-tute (FLI), Jena, Germany

Schuster, Stefan Friedrich Schiller University Jena, Germany

Sasso, Severin Friedrich Schiller University Jena, Germany

Figure 1: Relations of sys-tems biology approaches for biomarker discovery, network inference and module discov-ery. With the help of OMICS data, biomarkers can be identified that indicate patient conditions and may serve as diagnostic or prognostic mark-er. OMICS data are used for network inference, where, with support of prior knowledge, regulatory networks are recon-structed. These networks pre-dict novel molecular interac-tions as well as important key regulatory molecules, which may become novel therapeutic targets. The interaction network derived from prior knowledge forms the basisfor the discovery of disease modules. Creation of hypo-theses in this field is supported by OMICS data and/or known associations between diseases and molecules. All three ap-proaches require experimental validation of the generated hy-potheses, which then serve as new prior knowledge for future experiments and analyses.

(Source: Dix A et al. 2016, Clin Microbiol Infect 22(7), 600-606.)

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Schmidtke, Michaela University Hospital Jena, Germany

Zeilinger, Katrin Charité Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, Germany

SELECTED PUBLICATIONSDix A, Czakai K, Springer J, Fliesser M, Bonin M, Guthke R, Schmitt AL, Einsele H, Linde J, Löffler J (2016) Genome-wide expression profiling re-veals S100B as biomarker for invasive aspergil-losis. Front Microbiol 7, 320.

Guthke R, Gerber S, Conrad T, Vlaic S, Durmus S, Cakir T, Sevilgen E, Shelest E, Linde J (2016) Data-based reconstruction of gene regulatory networks of fungal pathogens. Front Microbiol 7, 570.

Linde J, Duggan S, Weber M, Horn F, Sieber P, Hellwig D, Riege K, Marz M, Martin R, Guthke R, Kurzai O (2015) Defining the transcriptomic landscape of Candida glabrata by RNA-Seq. Nu-cleic Acids Res 43, 1392-1406.

Priebe S, Kreisel C, Horn F, Guthke R, Linde J (2015) FungiFun2: A comprehensive online re-source for systematic analysis of gene lists from fungal species. Bioinformatics 31, 445-446.

THE RESEARCH GROUP IS DEDICATED TO THE INTEGRATED COMPUTATIONAL ANALYSIS OF GENOME, TRANSCRIPTOME, PROTEOME AND METABOLOME,

AS WELL AS MICROBIOLOGICAL AND CLINICAL DATA. CENTRAL TASKS ARE THE PRE-PROCESSING OF OMICS DATA, PREDICTION OF SECONDARY METABOLITES

AND MODELING OF HOST-FUNGUS INTERACTIONS.

Reinhard Guthke

Schulze S, Henkel SG, Driesch D, Guthke R, Linde J (2015) Computational prediction of molecular pathogen-host interactions based on dual tran-scriptome data. Front Microbiol 6, 65.

MAJOR THIRD PARTY FUNDINGBMBF Initiative GERONTOSYS – Jena Centre for Systems Biology of Ageing – JenAge – Sys-tems biology of mild stress in healthy ageing – a multi-species approach

BMBF Initiative GERONTOSYS – OXISYS – Role of oxidative injury in aging and therapeutic im-plications

BMBF Initiative Virtual Liver – Projects A1.1, A3.5, A3.6, B2.2, C3, C4

DFG Collaborative Research Centre 1127 Chem-BioSys – Project INF – Information Infrastruc-ture / Pattern Recognition

DFG Collaborative Research Centre / Transregio 124 FungiNet – Project B3 – Predictive modeling of host-fungal pathogen interactions by recon-struction of gene regulatory networks

DFG Collaborative Research Centre / Transregio 124 FungiNet – Project INF – Integrated data-base and standardised analysis of experimental data


Figure 2: Gene regulatory net-work inference – Workflow.Genes were selected based on their expression steady-state levels and their assigned function. RNA-Seq data and prior-knowledge were used as inputs for the NetGenerator. Using mathematical modeling, a network was predicted, which was then evaluated and tested for robustness. A final model was selected, which led to new hypotheses that were experi-mentally validated.

(Source: Altwasser R et al. 2015, PLOS One 10(9), e0136932)

INDEPENDENT JUNIORRESEARCH GROUP BIOBRICKS OF MICROBIALNATURAL PRODUCTSYNTHESES

64


Setting up a toolbox for studying natural products from eukaryotesFungi produce an inestimable number of nat-ural products. Unfortunately, the majority of fungal species are recalcitrant to standard lab conditions and genetic manipulation. A way to overcome these problems is the heterologous expression of entire gene clusters in amenable hosts. We recently developed a new technique based on the expression of polycistronic genes in eukaryotes. This technique takes the advan-tage of using 2A peptide sequences from Pi-cornaviruses, which are used to space out the different expressed genes.

In the last year this tool was implemented at dif-ferent levels:

ǿ Isolation and cloning of the genes of interest was simplified developing a very efficient plasmid assembly line;

ǿ We designed a fluorescent marker having two split GFP subunits, which releases flu-orescence only when reassembled in the nucleus. The two subunits are cloned at the beginning and at the end of the polycistronic gene; thus only those mutants having fluo-rescent nuclei express the entire cluster. This technical improvement decreases the possi-bility of selecting false positives to zero.

ǿ The 2A tags were manipulated in order to be removed after protein translation;

This tool is actually used to broadly investigate unknown gene clusters in fungi.

In vitro production of active moleculesPKS predominantly use malonyl-CoA extender units to build carbon skeletons. Some bacteria evolved an efficient method to produce this im-portant molecule using a single enzymatic step via malonyl-CoA synthases. The matB gene from Rhizobium leguminosarum was isolated and expressed in E. coli, and a recombinant protein was produced and purified. Activity assay con-firmed that MatB is a malonyl-CoA synthase that catalyses the malonyl-CoA formation by simply mixing sodium malonate, ATP and CoA.

R. leguminosarum express another gene, named as matA, which codes for a malonyl-CoA de-carboxylase. The matA gene product was also expressed and purified. MatA activity assay con-firmed that this enzyme catalyses the formation of acetyl-CoA by malonyl-CoA decarboxylation.

The activity of both purified enzymes was com-bined to produce acetyl-CoA out of Na-malonate. With this we are now able to produce either mal-onyl-CoA by MatB or acetyl-CoA by combining

INDEPENDENT JUNIOR RESEARCH GROUPBIOBRICKS OF MICROBIALNATURAL PRODUCT SYNTHESES


MatB and MatA activity starting from simple units such as sodium malonate and free CoA.

Increasing PKS extender unitconcentrations in fungi.Since the mat genes from R. leguminosarum showed high activity in vitro, we express those genes in S. cerevisiae to increase malonyl-CoA concentrations. In order to monitor malonyl-CoA production, we designed a Fap-derived sensor system controlling lacZ expression. Changes in malonyl-CoA are detected using the well-estab-lished beta-galactosidase activity assay. Once this system will be implemented, it will be used for the engineering of model fungi to better pro-duce polyketide derived secondary metabolites.

COLLABORATIONSFreier, Erik Leibniz Institute for Analytical Sciences (ISAS), Dortmund, Germany

Goldman, Gustavo University of Sao Paulo, Brasil

Thiele, Julian Leibniz Institute of Polymer Research (IPF), Dresden, Germany

OUR GROUP IS WORKING ON: 1) THE DEVELOPMENT OF A TOOLBOXFOR STUDYING NATURAL PRODUCTS FROM EUKARYOTES;

2) IDENTIFICATION AND ISOLATION OF ENZYMES TO REALIZE IN VITRO CELL-FREE BIOSYNTHETIC SYSTEM (MICROREACTORS); 3) IMPLEMENTING THE PRODUCTION

OF POLYKETIDE SYNTHASE (PKS) EXTENDER UNITS IN CHASSIS ORGANISMS.

Vito Valiante

SELECTED PUBLICATIONSValiante V, Baldin C, Hortschansky P, Jain R, Thywißen A, Straßburger M, Shelest E, Heinekamp T, Brakhage AA. (2016) The Aspergillus fumigatus co-nidial melanin production is regulated by the bifunctional bHLH DevR and MADS-box RlmA transcription factors. Mol Microbiol 102, 321-335.

Bruder Nascimento AC, Dos Reis TF, de Castro PA, Hori JI, Bom VL, de As-sis LJ, Ramalho LN, Rocha MC, Malavazi I, Brown NA, Valiante V, Brakhage AA, Hagiwara D, Goldman GH (2016) Mitogen activated protein kinases SakA(HOG1) and MpkC collaborate for Aspergillus fumigatus virulence. Mol Microbiol 100, 841-859.

Altwasser R, Baldin C, Weber J, Guthke R, Kniemeyer O, Brakhage AA, Linde J, Valiante V (2015) Network modeling reveals cross talk of map kinases during adaptation to caspofungin stress in Aspergillus fumigatus. PLOS One 10, e0136932.

Mattern DJ, Valiante V, Unkles SE, Brakhage AA (2015) Synthetic biology of fungal natural products. Front Microbiol 6, 775.

Valiante V, Macheleidt J, Föge M, Brakhage AA (2015) The Aspergillus fumi-gatus cell wall integrity signaling pathway: drug target, compensatory path-ways, and virulence. Front Microbiol 6, 325.

MAJOR THIRD PARTY FUNDINGBMBF Strategic Process Biotechnology 2020+ – Leibniz Research Cluster Bio/synthetic multifunctional micro production units – novel ways of com-pound development

INDEPENDENT JUNIORRESEARCH GROUP CHEMISTRY OF MICROBIALCOMMUNICATION

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We identified bacterial nonribosomal peptides that are crucial in the defense against amoebal predators. We elucidated their structures, syn-thesized them, investigated their biosynthesis, and investigated their biological activity and ecological function. We have now a variety of bioassays that allow to determine the effect of bacterial secondary metabolites on various soil amoebae. We then investigated the regulation of bacterial secondary metabolites that have an-ti-predator activity. In particular, we could show that anti-predator metabolites can be up-regu-lated in the presence of co-isolated bacteria.

We synthesized the eukaryotic signaling mol-ecule glorin (an amoebal chemoattractant, an acrasin) as well as analogues that are important in the development of eukaryotic multicellularity.We established the groundwork to perform ge-netic modifications in the social amoeba Dic-tyostelium discoideum. We could thus generate a mutant with an inactive polyketide synthase gene. The mutant was characterized with regard to its multicellular development. In addition, we performed first tests to implement the CRISPR/Cas9 technology in D. discoideum.

COLLABORATIONSQueller, David Washington University in St. Louis, USA

Strassmann, Joan Washington University in St. Louis, USA

Winckler, Thomas Friedrich Schiller University Jena, Germany

SELECTED PUBLICATIONSBraesel J, Götze S, Shah F, Heine D, Tauber J, Hertweck C, Tunlid A, Stallforth P, Hoffmeister D (2015) Three redundant synthetases secure redox-active pigments production in the basidio-mycete Paxillus involutus. Chem Biol 22,1325.

Götze S, Stallforth P (2015) Chemical communi-cation in microbial communities. GIT Lab J 11-12, 16.

Matthies S, Stallforth P, Seeberger PH (2015) Total synthesis of legionaminic acid as basis for serological studies. J Am Chem Soc 137, 2848.

Stallforth P, Clardy J, (2014) An atlas for drug dis-covery. Proc Natl Acad Sci USA 111, 3655.

Cavallari M*, Stallforth P*, Kalinichenko A*, Rath-well D, Gronewold TMA, Adibekian A, Mori L, Landmann R, Seeberger PH, DeLibero G (2014) A semi-synthetic carbohydrate-lipid vaccine that protects against S. pneumoniae in mice. Nat Chem Biol 10, 950. * authors contributed equally.

INDEPENDENT JUNIOR RESEARCH GROUPCHEMISTRY OF MICROBIAL COMMUNICATION


MAJOR THIRD PARTY FUNDINGAventis Foundation – The Roles of Eukaryotic Polyketides in Interspecies Interactions of Dic-tyostelium discoideum

Daimler and Benz Foundation – Deciphering the Chemical Communication Code in Symbiotic Eukaryote-Prokaryote Interactions

Dr. Illing Stiftung – Bioaktive Naturstoffe in Amöben-Bakterien Interaktionen

Fonds der Chemischen Industrie

THE MAIN GOAL OF OUR GROUP IS THE IDENTIFICATION AND BIOLOGICAL EVALUATION OF NATURAL PRODUCTS THAT PLAY CRUCIAL ROLES IN

EUKARYOTE-PROKARYOTE INTERACTIONS. WE ARE PARTICULARLY INTERESTED IN SCENARIOS IN WHICH BACTERIA HAVE TO DEFEND

THEMSELVES AGAINST PREDATORS USING SECONDARY METABOLITES.

Pierre Stallforth

Fruiting body of the social amoeba Dictyostelium dis-coideum.

INDEPENDENT JUNIORRESEARCH GROUP CHEMICAL BIOLOGY OFMICROBE-HOST INTERACTIONS

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Model system fungus-growing termitesFungus-growing insects rear in specialized combs a symbiotic fungus (Termitomyces) as a food source. Defensive symbionts support the homeostasis of the colony by secretion of selec-tive antimicrobial and antifungal products.

We have isolated a broad diversity of bacteria as-sociated with the fungus comb, the termite cuti-cle and the termite gut. All strains were evaluat-ed for their antimicrobial activity together with the Jena Microbial Resource Collection (JMRC), tested in bacteria-fungi interaction assays against fungus-garden antagonists (co-isolated fungi) and phylogenetically analyzed. Based on this profiling, two Actinobacteria strains were fully sequenced. Subsequent HRMS-based anal-ysis of co-culture extracts led to two promising molecular candidates, which are now structural-ly analyzed.

We have isolated several co-evolved fungal an-tagonists (Pseudoxylaria), which were tested in fungus-fungus paired challenge assays for their antifungal activity. Zones of inhibition were ana-lyzed using MALDI Imaging. MS-based differen-tial metabolomics led to the isolation of several

new cyclic tetrapeptides with an unusual allene modification. We are currently exploring the pro-miscuity of the NRPS machinery with respect to commercial and synthetic amino acid deriv-atives.

Using field samples, we are currently analyzing the chemical environment of the termite gut. After dissection, termite guts were pooled and extracted using solid phase extraction methods. We are currently establishing a reliable purifica-tion protocol to analyze the dominant metabo-lites.

Model system Hydractinia echinataThe life cycle of the marine hydroid polyp Hydrac-tinia echinata has a motile (larvae) and sessile re-productive phase (polyp). The metamorphosis of the larvae is induced by compounds of the biofilm produced by specific bacterial species (Pseudoalteromonas spp).

We aim to identify the bacterial molecular cues and the receptor in the marine hydroid polyp to understand the interaction mechanisms in more detail. We have established a bacterial collection of inducing and non-inducing bacterial strains; some of which were genome-sequenced. Based on activity profiling, we currently concentrate on strain P1-9 (sequenced). Using bioassay-guid-ed fractionation, we are currently purifying the active substance(s). First NMR-studies of ac-tive fractions indicate a sugar-type of molecule, which might be responsible for the observed effect.

We have also profiled the bacterial and fungal collection isolated from Hydractinia echinata. An-timicrobial-activity assays led to the isolation of several new molecules, including a new indole derivative.

Total synthesis of chemical signals induc-ing morphogenesis in choanoflagellates Based on previously published work, we are cur-

INDEPENDENT JUNIOR RESEARCH GROUPCHEMICAL BIOLOGYOF MICROBE-HOST INTERACTIONS


rently establishing a total synthesis of a highly active sulfonolipid and derivatives thereof. Here we aim to establish the absolute structure, in-stall fluoresence tags and photolable tags to identify the enzymatic target.

In collaboration with the group of Axel Brakhage, we are synthesizing the fungal metabolite sphin-gofungin and derivatives thereof using a novel, and highly atom-economic synthetic approach.

COLLABORATIONSAlegado, Rosanna University of Hawaii, Honolulu, USA

Clardy, John Harvard Medical School, Boston, USA

Hadfield, Mike University of Hawaii, Honolulu, USA

Kim, Ki-Hyun Sungkyunkwan University Suwon, Republic of Korea

Poulsen, Michael University of Copenhagen, Denmark

Wingfield, Mike University of Pretoria, South Africa

SELECTED PUBLICATIONSKim KH, Ramadhar TR, Beemelmanns C, Cao S, Poulsen M, Currie CR, Clardy J (2014) Natalamy-cin A, an ansamycin from a termite-associated Streptomyces sp. Chem Sci 5, 4333-4338.

OUR GROUP FOCUSES ON THE ANALYSIS OF DEFENSIVE SECONDARY METABOLITES AND CHEMICAL SIGNALS WITH MORPHOGENIC PROPERTIES OF

TWO MODEL SYSTEMS. MAJOR AIM IS THE FULL STRUCTURAL ELUCIDATION BY ANALYTICAL AND SYNTHETIC METHODS AS WELL AS THE ELUCIDATION OF

THE BIOSYNTHETIC PATHWAY.

Christine Beemelmanns

Ramadhar TR, Beemelmanns C, Currie CR, Clardy J (2014) Bacterial symbi-onts in agricultural systems provide a strategic source for antibiotic discov-ery. J Antibiot (Tokyo) 67, 53-58.

Klassen JL, Wolf T, Rischer M, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Draft genome sequences of six Pseudoalteromonas sp. strains P1-7a, P1-9, P1-13-1a, P1-16-1b, P1-25 and P1-26, which induce larval settlement and metamorphosis in Hydractinia echinata. Genome Announc 3, e01477-15.

Klassen JL, Rischer M, Wolf T, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Genome sequences of three Pseudoalteromonas strains P1-8, P1-11 and P1-30 isolated from the marine hydroid Hydractinia echinata. Genome Announc 3, e01380-15.

Beemelmanns C, Woznica A, Alegado RA, Cantley AM, King N, Clardy J (2014) Synthesis of the rosette-inducing factor RIF-1 and analogs. J Am Chem Soc 136, 10210-10213.

MAJOR THIRD PARTY FUNDINGDaimler and Benz Foundation – Exploring the Chemical Potential of Ter-mite-associated Bacteria

INDEPENDENT JUNIORRESEARCH GROUP SECONDARY METABOLISMOF PREDATORY BACTERIA

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The predatory myxobacterium Pyxidicoccus fal-lax, which had been isolated from the shores of the river Saale, exhibits a narrow prey range that is restricted to Gram-positive bacteria. Bioactivi-ty-guided fractionation enabled the discovery of the gulmirecins, which represent a new class of

macrolide antibiotics with potent activity against methicillin-resistant staphylococci. Subsequent studies involving label incorporation into DNA, RNA, protein and cell wall biosynthesis revealed the bacterial RNA polymerase as their molecular target.

Although the activity spectrum of the gulmire-cins was consistent with the bacterial prey spec-trum of P. fallax, it did not explain the observed predation of eukaryotic microorganisms. The bioactivity testing was hence expanded, which eventually led to the isolation of an antiprolifera-tive compound with preferential activity against leukemic cells. The metabolite was identified as the known siderophore myxochelin A and its antileukemic properties were traced to an inhibition of human 5-lipoxygenase. Afterwards several myxochelin derivatives were generated by precursor-directed biosynthesis. Testing of these analogs indicated that the antileukemic activities can be decoupled from the iron-chelat-ing properties. This discovery prompted efforts to develop a synthetic strategy for the prepa-ration of myxochelins, which recently allowed their commercial distribution via AdipoGen Life Sciences.

A genome mining study in Herpetosiphon au-rantiacus led to the isolation of a novel PKS/NRPS-derived natural product, thereby provid-ing the first evidence for the previously assumed biosynthetic potential of this micropredator. Furthermore, new myxothiazol derivatives were retrieved from the myxobacterium Myxococcus fulvus. The group also designed and validated a new assay to quantify the killing and consump-tion of prey organisms by predatory bacteria.

INDEPENDENT JUNIOR RESEARCH GROUPSECONDARY METABOLISMOF PREDATORY BACTERIA


Isolation of soil bacteria and determination of their predatoryactivity (upper row), organization of the auriculamide genecluster and assembly line in the predatory bacteriumHerpetosiphon aurantiacus (middle row), biochemical andchemical dissection of auriculamide biosynthesis (lower row).

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COLLABORATIONSBryant, Donald Pennsylvania State University, USA

Gross, Harald University of Tübingen, Germany

König, Gabriele University of Bonn, Germany

Kost, Christian Max Planck Institute for Chemical Ecology, Jena, Germany

Kovács, Ákos Friedrich Schiller University Jena, Germany

Müller, Rolf Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany

Tosin, Manuela University of Warwick, UK

Werz, Oliver Friedrich Schiller University Jena, Germany

SELECTED PUBLICATIONSSchieferdecker S, König S, Weigel C, Dahse H-M, Werz O, Nett M (2014) Structure and biosynthet-ic assembly of gulmirecins, macrolide antibiot-ics from the predatory bacterium Pyxidicoccus fallax. Chem Eur J 20, 15933-15940.

OUR RESEARCH AIMS AT EXPLOITING PREDATORY BACTERIA AS A NOVEL SOURCE OF URGENTLY NEEDED ANTIBIOTICS. FOR THIS, WE EVALUATE

THE BIOSYNTHETIC POTENTIAL OF THESE ORGANISMS USING OMICS TOOLS. MAJOR OBJECTIVES ARE TO IDENTIFY NOVEL NATURAL PRODUCTS

AND TO ENGINEER THEIR BIOSYNTHETIC PATHWAYS.

Markus Nett

Schieferdecker S, König S, Koeberle A, Dahse H-M, Werz O, Nett M (2015) Myxochelins target human 5-lipoxygenase. J Nat Prod 78, 335-338.

Korp J, König S, Schieferdecker S, Dahse H-M, König GM, Werz O, Nett M (2015) Harnessing en-zymatic promiscuity in myxochelin biosynthesis for the production of 5-lipoyxygenase inhibitors. ChemBioChem 16, 2445-2450.

Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and ab-solute configuration of auriculamide, a natural product from the predatory bacterium Herpetosi-phon aurantiacus. Eur J Org Chem 14, 3057-3062.

Kage H, Riva E, Parascandolo JS, Kreutzer MF, Tosin M, Nett M (2015) Chemical chain termi-nation resolves the timing of ketoreduction in a partially reducing iterative type I polyketide syn-thase. Org Biomol Chem 13, 11414-11417.

MAJOR THIRD PARTY FUNDINGDFG Collaborative Research Centre 1127 Chem-BioSys – Project B06 – Photoresponsive modu-lation of a freshwater phytoplankton community by bacterial lipopeptides

CROSS-SECTIONAL UNIT BIO PILOT PLANT

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Droplet microfluidics for ultra-high throughput screeningThe increasing occurrence and spread of mul-tidrug-resistant pathogens is a big problem. Innovative and effective approaches to discov-er novel antimicrobial compounds especially against Gram-negative and fungal pathogens are urgently needed.

To perform ultra-high throughput screenings for the detection of microorganisms producing anti-microbial compounds or highly active enzymes we are developing and using a droplet-microflu-idic platform. Starting from the established plat-form comprising all fundamental unit operations for the manipulation of surfactant-stabilized droplets (volume 100-200 picoliter), the next steps were to include biological processes into the workflow.

Substantial and reproducible growth of various bacteria inside droplets had to be realized in or-der to use droplets for antibiotic activity assess-ment of microorganisms derived from natural samples. Especially the production of secondary metabolites like antimicrobials depends on cell signals that are stimulated by specific cell den-

sities making it necessary to culture microbes in droplets for detecting antibiotic producers.

To achieve similar growth rates and biomass yields in droplets as in shaking flasks, we de-veloped and validated a system for dynamic droplet incubation (Mahler et al., 2015) allowing an enhanced and homogeneous oxygen sup-ply for very large droplet populations of up to 7 million droplets over time periods from days to months. By collecting droplets in a 3D-printed storage device, which is coupled into an oil re-circulation circle, a continuous flow of perfluori-nated oil through the droplet population can be maintained. This results in a continuous mixing of droplets and homogeneous conditions in all droplets. Thereby the oil surrounding the droplets is constantly replenished with dissolved oxygen. By employing this incubation method the oxy-gen transfer rate into droplets is highly improved as measured with nanoparticle sensors loaded with an oxygen-sensitive NIR-luminescence dye (Torsten Mayr, Graz). Furthermore, a bene-ficial effect of higher oxygen supply could also be seen in significantly enhanced cell growth for many biotechnologically relevant microorganisms as well as fastidious organisms previ-ously isolated from soil, and drastically elevated protein yields during heterologous gene expres-sion in droplets.

Several proof of principle studies were success-fully performed for enzyme screenings taking advantage of the increased and reliable signals caused by cell replication in droplets. By using known strains expressing lipases, esterases or amylases, positive clones could be detected and enriched.

Furthermore, the detection of antimicrobials was achieved by monitoring the survival of re-porter bacteria that were added to antibiotic producing bacteria. A robust discrimination be-tween droplets containing a strain producing inhibiting compounds and a strain that is not

CROSS-SECTIONAL UNIT BIO PILOT PLANT


producing was accomplished. Now the assay is applied to unknown bacterial communities de-rived from natural samples.

Discovery of secondary metabolites from an-aerobic and other neglected bacteriaCurrent genome mining approaches (Depart-ment Biomolecular Chemistry) revealed the potential of anaerobic bacteria to produce so far unknown secondary metabolites. In collab-oration with the department BMC we cultured numerous strictly anaerobic bacterial species in lab-scale bioreactors (1-7 L) using a variety of media. The variation of culture conditions resulted in the discovery of clostrubins A and B, exceptional polyphenolic polyketide antibiotics produced by plant-pathogenic clostridia.

In collaboration with the junior research group Secondary Metabolism of Predatory Bacteria new natural products from myxobacteria and predatory bacteria (auriculamide, myxothiazol derivatives) were found.

The analysis and quantification of substrates, metabolites and products is an integrated part of bioprocess development and optimization. Production of biomolecules can be affected by target oriented substrate feeding. Besides the analysis of carbohydrates, nitrogen and phos-phorus, HPLC and GC/MS are used to get infor-mation about the metabolic state of bioprocess-es. Development of analytical methods is done in collaboration with departments of the HKI and companies.

Optimization of downstream and purification processes for antibodiesNew therapies and diagnostics have a high de-mand for recombinant antibodies. Efficient ex-pression systems are needed for the production of these antibodies. However, the concentration of target proteins in inclusion bodies implies the risk of losing the biological function caused by renaturation and refolding procedures. There-

fore the optimization of production processes and especially the downstream processing is a challenge. In collaboration with an industrial partner upstream and downstream processes for the production of biologically active proteins were analyzed to improve the process scalability and the yield of soluble and biologically active protein.

Fab fragments were produced as model antibod-ies in a high cell-density fermentation process by a recombinant E. coli strain. After fermentation, preparation of cell lysate and two-step clarifica-tion, an ion exchange chromatographic process for the capture of the proteins was evaluated instead of the current standard affinity chroma-tography. The produced Fab antibodies were further used as a standard for characterization of a novel chromatographic resin and the scale-up of the whole process to the pilot scale. The influence of ionic strength und pH of the sample on the capacity of the chromatographic resin was tested. Dynamic loading rate and selectivi-ty of the chromatographic resin were examined. A biologically active product of high quality was finally achieved by a single ion exchange chro-matography step.

COLLABORATIONSFändrich, Marcus University of Ulm, Germany

König, Gabriele University of Bonn, Germany

Mayr, Torsten Technical University of Graz, Austria

BioControl Jena GmbH, Germany

Dyomics GmbH, Jena, Germany

Heidelberg Pharma Research GmbH, Germany

Lasos Lasertechnik GmbH, Jena, Germany

Tepha Medical Devices Inc., USA

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SELECTED PUBLICATIONSMahler L, Tovar M, Weber T, Brandes S, Rudolph M M, Ehgartner J, Mayr T, Figge MT, Roth M, Zang E (2015) Enhanced and homogenous oxy-gen availability during incubation of microfluidic droplets. RSC Advances 5, 101871-101878.

Funk J, Schaarschmidt B, Slesiona S, Hallström T, Horn U, Brock M (2016) The glycolytic enzyme enolase represents a plasminogen-binding pro-tein on the surface of a wide variety of medical-ly important fungal species. Int J Med Microbiol 306, 59-68.

Shabuer G, Ishida K, Pidot SJ, Roth M, Dahse HM, Hertweck C (2015) Plant pathogenic an-aerobic bacteria use aromatic polyketides to access aerobic territory. Science 350, 670-674.

Wulff M, Baumann M, Thümmler A, Yadav JK, Heinrich L, Knüpfer U, Schlenzig D, Schierhorn A, Rahfeld JU, Horn U, Balbach J, Demuth HU, Fändrich M (2016) Enhanced fibril fragmenta-tion of n-terminally truncated and pyroglutam-yl-modified Aβ peptides. Angew Chem Int Ed 55, 5081-5084.

Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and ab-solute configuration of auriculamide, a natural product from the predatory bacterium Herpetosi-phon aurantiacus. Eur J Org Chem 14, 3057-3062.

MAJOR THIRD PARTY FUNDINGFree State of Thuringia – Microfluidic platform technology for ultra-high throughput screening of novel antimicrobial compounds from micro-organisms, DropCode

Tepha Medical Devices, Lexington, USA – De-velopment and optimization of fermentation and downstream processes for the production of polyhydroxyalkanoates for medical applications

IN THE BIO PILOT PLANT WE USE INNOVATIVE TECHNOLOGIES FOR SCREENING LARGE AND DIVERSE POPULATIONS OF MICROBES TO SELECT PRODUCERS

OF NOVEL ANTIMICROBIAL COMPOUNDS AND ENZYMES, AND DEVELOP FERMENTATION AND DOWNSTREAM PROCESSES FOR THE PRODUCTION OF

ANTIBIOTICS, ENZYMES, ANTIBODIES, TOXINS AND BIOPOLYMERS.

Uwe Horn

CROSS-SECTIONAL UNIT JMRC – JENA MICROBIALRESOURCE COLLECTION

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Mucormycoses are emerging fungal infections in immunocompromized patients. They range among the four most important infections caused by fungi in human with respect to report-ed cases worldwide. The main route of the infec-tion is via the respiratory tract and alveolar mac-rophages (AM) represent the first line of defence in pulmonary infections. Lichtheimia corymbifera is one of the most common agents of mucormy-coses. It does not form hyphae but persists long-term in alveolar macrophages by hampering the phagolysosomal fusion, a critical step for intra-cellular killing of pathogens by immune cells of the innate immune system. The structure of the spore surface appears to contribute to the ratio of phagocytosis, particularly under opsonized conditions that render the pathogen susceptible to phagocytosis. Virulence correlates with higher opsonin binding and presentation of the hydro-phobic surface protein HSB-A. Masking macro-phages with HSB-A revealed decreased phago-cytosis indicating the contribution of HSB-A as ligand in the recognition by the host. Additional-ly, glucans are the predominant components in

the fungal cell wall. Recognition is dectin-1 inde-pendent. At the genome level, L. corymbifera has a genome size of 33.6 Mb, 12,379 protein-coding genes and low content of repetitive elements. Extensive gene duplications create functional-ly diverse paralogs independently of whole ge-nome duplication. The genus-wide genomic and transcriptomic profiling indicates that pathogen-ic and non-pathogenic Lichtheimia species have the genetic inventory enabling them to cause in-fections, but pathogenic species differ in stress tolerance at elevated temperatures. The stress response appears to be vulnerable and can be altered by the presence of additional stresses leading to a growth recovery of non-pathogenic L. hyalospora which was evidenced to be inde-pendent of the high osmolarity glycerol (HOG) pathway. The ability of pathogenic Lichtheimia species to cope with the accumulation of mis-folded proteins contributes to fast growth at elevated temperatures and their ability to cause human infections. The incapability of non-patho-genic species to degrade misfolded proteins un-der virulence-related stress conditions causes a protein conformational disorder resulting in fun-gal damage and attenuation.

CROSS-SECTIONAL UNITJMRC – JENA MICROBIAL RESOURCECOLLECTION


Scanning electron micropho-tograph of a mature sporan-giospore from Lichtheimia corymbiferaJMRC:SF:00938.

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OUR AIM IS THE MAINTENANCE OF MICROORGANISMS, SURVEY OF ANTIMICROBIAL ACTIVITIES OF NATURAL PRODUCTS AND DECIPHERING

THE PATHOGENICITY MECHANISMS OF ZYGOMYCETES AT GENOMIC, TRANSCRIPTOMIC, PROTEOMIC AND CELLULAR LEVEL WITH SUBSEQUENT

PROOF IN INVERTEBRATE, AVIAN AND MAMMALIAN INFECTION MODELS.

Kerstin Voigt

COLLABORATIONSGabaldon, Toni Centre for Genomic Regulation Barcelona, Spain

Grigoriev, Igor V. DOE Joint Genome Institute, Walnut Creek, CA, USA

Lass-Flörl, Cornelia Medical University Innsbruck, Austria

Molinario, Antonio University of Napoli Federico II, Italy

Papp, Tamás University of Szeged, Hungary

SELECTED PUBLICATIONSGrützmann K, Szafranski K, Pohl M, Voigt K, Petzold A, Schuster S (2014) Fungal alternative splicing is associated with multicellular com-plexity and virulence: a genome-wide multi-spe-cies study. DNA Res 21, 27-39.

Kaerger K, Schwartze VU, Dolatabadi S, Nyilasi I, Kovács S, Binder U, Papp T, de Hoog S, Jacobsen ID, Voigt K (2015) Adaptation to thermotolerance in Rhizopus coincides with virulence as revealed by avian and invertebrate infection models, phy-logeny, physiological and metabolic flexibility. Virulence 6, 395-403.

Kraibooj K*, Park HR*, Dahse HM, Skerka C, Voigt K+, Figge MT+ (2014) Virulent strain of Lichtheimia corymbifera shows increased phagocytosis by macrophages as revealed by automated micros-copy image analysis. Mycoses 57, Suppl. 3, 56-66, */+authors contributed equally.

Park HR, Voigt K (2014) Interaction of Zygomy-cetes with innate immune cells reconsidered with respect to ecology, morphology, evolution and infection biology: a mini-review. Mycoses 57, Suppl. 3, 31-39.


Schwartze VU, Winter S, Shelest E, Marcet-Hou-ben M, Horn F, Wehner S, Linde J, Valiante V, Sammeth M, Riege K, Nowrousian M, Kaerger K, Jacobsen ID, Marz M, Brakhage AA, Gabaldón T, Böcker S, Voigt K (2014) Gene expansion shapes genome architecture in the human pathogen Lichtheimia corymbifera: an evolutionary genom-ics analysis in the ancient terrestrial Mucorales (Mucoromycotina). PLOS Genetics 10, e1004496.

MAJOR THIRD PARTY FUNDINGBMBF Project in Collaboration with Hungary – Gene silencing in human pathogenic zygomy-cetes

DFG Collaborative Research Centre / Transre-gio 124 FungiNet – Project Z1 – The regulatory role putative virulence determinants of human pathogenic zygomycetes based on RNAseq analyses

CROSS-SECTIONAL UNIT ILRS – INTERNATIONALLEIBNIZ RESEARCHSCHOOL

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The International Leibniz Research School for Mi-crobial and Biomolecular Interactions (ILRS) as graduate school of the HKI offers cutting edge doctoral research projects in close collaboration with the Friedrich Schiller University Jena, the University Hospital Jena and the Max Planck In-stitute for Chemical Ecology. Currently, around 60 doctoral researchers from 12 different coun-tries pursue their PhD projects in microbiology, natural product chemistry, infection biology, bioinformatics or systems biology within the framework of ILRS. Since 2014, all doctoral re-searchers at the HKI benefit from the structured graduate training.

The ILRS curriculum consists of: ǿ Annual symposia and regular group seminars ǿ Annual Thesis Committee Meetings with the

team of mentors ǿ Practical courses in advanced scientific

techniques offered by ILRS faculty members ǿ An extensive selection of transferable skills

courses, career orientation seminars and language courses

ǿ Presenting the ILRS research topics to the public (e.g. during the Long Night of Scienc-es or Pupils’ Resarch Day)

ǿ Social activities for informal exchange and networking.

The ILRS closely works together with the other graduate schools in the field of microbiology in Jena under the umbrella of the excellence grad-uate school Jena School for Microbial Communi-cation (JSMC).

ILRS doctoral researchers not only publish their results in renowned journals, they also frequent-ly receive external recognition for their work, e.g. the PhD award of the Faculty of Biology and Pharmacy for Chen Qian. The individual contri-butions are listed in the sections of the respec-tive structural units.

All information about the projects, events and news are available on the ILRS website which was completely revised in 2015 and is now avail-able at www.ilrs.de.

CROSS-SECTIONAL UNIT ILRS – INTERNATIONAL LEIBNIZ RESEARCH SCHOOL


THE ILRS OFFERS EXCELLENT STRUCTURED GRADUATE TRAINING FOR DOCTORAL RESEARCHERS, COMBINING

AMBITIOUS RESEARCH PROJECTS WITH ASTATE-OF-THE-ART QUALIFICATION PROGRAM IN

LABORATORY METHODS AND TRANSFERABLE SKILLS.

Peter Zipfel

ILRS SCIENTIFIC ADVISORY BOARDProf. Gerhard Bringmann (Julius-Maximilians-Universität Würzburg)

Prof. Sven Hammerschmidt (Universität Greifswald)

Prof. Petra Dersch (Helmholtz-Zentrum für Infektionsforschung, Braunschweig)

Prof. Kristian Riesbeck (Lund University, Schweden)

ILRS STEERING COMMITTEEPeter F. Zipfel (spokesperson, HKI, Infection Biology)

Ian T. Baldwin (Max Planck Institute for Chemical Ecology)

Christine Beemelmanns (HKI, Chemical Biology of Host-Microbe Interactions)

Gabriele Diekert (Friedrich Schiller University)

Berhard Hube (HKI, Microbial Pathogenicity Mechanisms)

Dirk Hoffmeister (Friedrich Schiller University)

ILRS REPRESENTATIVESUntil 2015:

Juliane Fischer (HKI, Molecular and Applied Microbiology)

Daniel Schwenk (Friedrich Schiller University)

Since 2015:

Jens Esken (Friedrich Schiller University)

Benjamin Hanf (HKI, Molecular and Applied Microbiology)

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Figure 1: During the Pupils’ Research Day (“Forsche Schüler Tag”) ILRS doctoral researcher Christine Dunker lets high school students join in her work in a microbiology research lab.


Figure 2: At the annual ILRS Symposium 2015, ILRS spokesperson Peter F. Zipfel (right) congratulates Susanne Brandes, Denise Buhlmann, Srividhya Sundaram, Franziska Gerwien and Justus Linden (from left to right) for receiving the awards for the best pre-sentations.

ASSOCIATED GROUP INFECTIONS INHEMATOLOGY/ ONCOLOGY

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Since febrile neutropenia (FN) is a major threat in cancer patients, our group works on improv-ing prophylaxis and treatment of cancer patients with fever. Currently, we concentrate on optimis-ing empirical antibiotic therapy of FN. In a pilot study with 58 cancer patients we found sub-therapeutic levels of piperacillin/tazobactam in the majority of patients which might explain the

high failure rate of the antibiotic. Consequently, we have set up a randomized prospective trial to test the efficacy of therapeutic drug monitoring of piperacillin / tazobactam in FN. The study will start recruiting in September 2016.

A special focus of our group lies on the research of infections with community acquired respira-tory viruses (CARV). We have conducted a pro-spective monocentre diagnostic study on the epidemiology and relevance of CARV in healthy persons and patients after allogeneic stem cell transplantation during the winter months 2013 / 2014, 2014 / 2015 and 2015 / 2016. Throat gargles from 232 healthy persons and 161 pa-tients after allo-SCT were tested regardless of current symptoms. Twenty-four percent of pa-tients and 9 % of healthy persons had at least one positive result, but patients took much lon-ger to clear the virus (up to 64 days of asymp-tomatic shedding). In addition, we conducted a multicentre retrospective study on influenza in cancer patients during the season 2014 / 2015 in 8 university hospitals in Germany. In total, 203 patients were included, 67 (33 %) of which had pneumonia. Altogether, 16 (8 %) patients died, all with pneumonia. Independent risk-factors for a fatal outcome of influenza-infection in cancer patients were bacterial/fungal superinfection (hazard ratio 3.4 95 % CI 1.09-10.6) and long du-ration until diagnosis (HR 1-1 95 % CI 1.01-1.2) but not activity/type of underlying malignancy or ongoing immunosuppression.

ASSOCIATED GROUPINFECTIONS IN HEMATOLOGY/ ONCOLOGY


A) Leukocytes are co-incubated with FITC-labelled wildtypeA. fumigatus conidia (green) and then counterstained with APC (red). B) Flowcytometry can distinguish bystander cells (Q4), cells with internalized conidia (Q3) and cells with attached/internalized conidia (Q2). C) Neutrophils from immunosuppressed patients exhibit a signifi-cantly reduced rate of phagocytosis (Q3). D) Aspergillus fumigatus influences the activation and migratory capacity of neutrophils with internalized conidia (Q3) and of by-stander cells (Q4). Here, downregulation of the adhesion molecule CD62L in phagocytosing (Q3) and bystander (Q4) cells is shown.

Aspergillus is one of the most dangerous patho-gens for immunosuppressed cancer patients. Of interest, invasive Aspergillus-infections do not only occur in neutropenic patients. This leads us to investigate the interaction of leukocytes from patients and controls with Aspergillus fumigatus. We found a reduced rate of phagocytosis by neu-trophil granulocytes from patients and an immu-nosuppressive effect of Aspergillus on phagocy-tosing as well as bystander cells (figure 1). We are currently working on unraveling the degree and immunological relevance of the disruptive effect of Aspergillus fumigatus on phagocytes.

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OUR RESEARCH GROUP AIMS AT UNRAVELINGEPIDEMIOLOGY AND PATHOPHYSIOLOGY

OF RELEVANT INFECTIONS IN PATIENTS WITHMALIGNANT DISEASES.

Marie von Lilienfeld-Toal

COLLABORATIONSInfectious Disease Working Party of the German Society for Hematology and Oncology (DGHO)

SELECTED PUBLICATIONSBusch A, Zeh D, Janzen V, Mügge LO, Wolf D, Fingerhut L, Hahn-Ast C, Maurer O, Brossart P, von Lilienfeld-Toal M (2014) Treatment with lena-lidomide induces immunoactivating and count-er-regulatory immunosuppressive changes in myeloma patients. Clin Exp Immunol 177, 439-453.

Mayer K, Hahn-Ast C, Mückter S, Schmitz A, Krause S, Felder L, Bekeredjian-Ding I, Molitor E, Brossart P, von Lilienfeld-Toal M (2015) Compari-son of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia. Support Care Cancer 23, 1321-1329.

Schnetzke U, Spies-Weisshart B, Yomade O, Fischer M, Rachow T, Schrenk K, Glaser A, von Lilienfeld-Toal M, Hochhaus A, Scholl S (2015) Polymorphisms of toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16, 83-88.

Schrenk KG, Schnetzke U, Stegemann K, von Lilienfeld-Toal M, Hochhaus A, Scholl S (2015) Efficacy of antifungal prophylaxis with oral sus-pension posaconazole during induction chemo-therapy of acute myeloid leukemia. J Cancer Res Clin Oncol 141, 1661-1668

Schwab KS, Hahn-Ast C, Heinz WJ, Germing U, Egerer G, Glasmacher A, Leyendecker C, Marklein G, Nellessen CM, Brossart P, von Lil-ienfeld-Toal M (2014) Tigecycline in febrile neu-tropenic patients with haematological malignan-cies: a retrospective case documentation in four university hospitals. Infection 42, 97-104.

MAJOR THIRD PARTY FUNDINGBMBF InfectoGnostics Research Campus – New diagnostic tools for pneumonia in immuno-suppressed patients

BMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC) – Therapeutic drug monitoring for personalized antibiotic treatment with piperacillin-tazobac-tam in patients with febrile neutropenia, Tar-get-FN

Deutsche Jose Carreras-Leukämiestiftung – Respiratory viruses in patients after allogeneic stem cell transplantation

ASSOCIATED GROUP MICROBIAL BIOCHEMISTRYAND PHYSIOLOGY

106


While most fungal species utilize the methylci-trate cycle for detoxification of propionyl-CoA, this pathway is not present in Candida albicans. We discovered that this dimorphic pathogen uses a modified beta-oxidation pathway for propionyl-CoA degradation. This may provide a special advantage when odd-chain fatty acids are utilized and could depict an adaptation to nu-trient provision from the infected host.

To monitor C. albicans infections and to visualize therapeutic efficacy, a bioluminescence imaging system was developed. Indeed, disease pro-gression, fungal dissemination and therapeutic success was reliably visualized. Unexpectedly, monitoring of antifungal therapy detected fun-gal persistence in the gall bladder with live C. albicans shed by feces. In the human host cells persisting in such cryptic niches may cause a re-colonization of the intestine after discontinu-ation of antifungal treatment. Reduced suscep-tibility of C. albicans in bile was confirmed by in vitro studies in which bile protected C. albicans from the major classes of antifungals used in therapeutic approaches. Therefore, special at-tention should be given to gall bladder infections under antifungal therapy.

In terms of secondary metabolite production we continued research on the natural product terrein that is produced in gram scales by the fil-amentous fungus Aspergillus terreus. We discov-ered an excellent correlation between signals inducing the terrein biosynthesis gene cluster and biological activities of terrein. Terrein is pro-duced under either nitrogen limitation, iron star-vation or the presence of methionine, which are common signals in the rhizosphere. In turn, ter-rein has phytotoxic and antifungal activities and reduces ferric to ferrous iron. These actions can increase availability of nutrients while simultane-ously inhibiting competitors.

ASSOCIATED GROUPMICROBIAL BIOCHEMISTRY AND PHYSIOLOGY


OUR GROUP FOCUSES ON PRIMARY AND SECONDARY METABOLISM OF OPPORTUNISTIC PATHOGENIC FUNGI. WE INVESTIGATE THE METABOLIC

FLEXIBILITY OF FUNGAL SPECIES, STUDY SIGNALS THAT INDUCE SECONDARY METABOLITE PRODUCTION AND VISUALIZE INFECTION PROCESSES BY

BIOLUMINESCENCE IMAGING.

Matthias Brock

A) Inoculation of cherries with Aspergillus terreus conidia suspension for identification of phytotoxins. B) Bioluminescence from the gall bladder of a mouse infect-ed with Candida albicans and kept under antifungal therapy.

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The high terrein production rates tempted us to investigate the transcriptional regulation of this biosynthesis gene cluster. A specific tran-scription factor called TerR controls expression of all genes involved in terrein biosynthesis. In agreement, all promoter regions within the clus-ter contain specific binding motifs that are rec-ognized by TerR. Due to the exceptional high ex-pression rates obtained from the combination of TerR with one of the cluster specific promoters (PterA), we developed a heterologous expression system in Aspergillus niger that is based on these terrein cluster elements. In this system, TerR does not induce gene expression in Aspergillus niger, which maintains low background signals in metabolite profiling. In recombinant metab-olite production the system was highly suitable for expression of fungal polyketide synthases and allowed the identification of lecanoric acid as metabolite product from Aspergillus nidulans OrsA. Vector sets and recipient strains are cur-rently optimized to allow for efficient cloning and expression of secondary metabolite gene clusters from a wide variety of fungal species.

COLLABORATIONSBeilhack, Andreas University Hospital Würzburg, Germany

Heinze, Katrin Julius Maximilians University Würzburg, Germany

Ibrahim-Granet, Oumaima Institut Pasteur, Paris, France

SELECTED PUBLICATIONSGressler M, Meyer F, Heine D, Hortschansky P, Hertweck C, Brock M (2015) Phytotoxin production in Aspergillus terreus is regulated by independent en-vironmental signals. eLife 4, pii: e07861.

Gressler M, Hortschansky P, Geib E, Brock M (2015) A new high-performance heterologous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front Microbiol 6, 184.

Jacobsen I, Lüttich A, Kurzai O, Hube B, Brock M (2014) In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy. J Antimicrob Chemo-ther 69, 2785-2796.

Otzen C, Bardl B, Jacobsen ID, Nett M, Brock M (2014) Candida albicans utilizes a modified β-oxidation pathway for the degradation of toxic propi-onyl-CoA. J Biol Chem 289, 8151-8169.

Zaehle C, Gressler M, Shelest E, Geib E, Hertweck C, Brock M (2014) Terrein biosynthesis in Aspergillus terreus and its impact on phytotoxicity. Chem Biol 21, 719-31.

MAJOR THIRD PARTY FUNDINGDFG Collaborative Research Centre / Transregio 124 FungiNet – Project A3 – In vivo analysis of temporal and spatial disease progression and immune cell recruitment during invasive Aspergillus fumigatus infection

DFG Project – Aspergillus terreus as a cause of invasive aspergillosis: Im-pact of secondary metabolites on pathogenesis

ASSOCIATED GROUP NETWORK MODELING

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High throughput methods of functional genomics produce massive data on a genome wide scale for a large variety of different organisms, organs and diseases. This information needs to be funneled and organized into a medically transferrable context. Our main focus is to improve diagnosis and therapy of systemic infections, and in its extreme, sepsis. Basing on data from high throughput methods from functional genomics, we aim to understand the molecular context of the immune response to systemic infections employing machine learning and network based models. In ad-dition, we are developing and using our methods to investigate aberrant regulation of tumor cells. Methodologically, we develop and transfer Mixed Integer Liner Programming (MILP) based solutions into bioinformatics.

We set up a coupled machine learning approach to estimate the quality of cytokine signaling using time lapse images of a high throughput knock-down screen (Suratanee et al., 2014). In this study, we used MILP to optimal-ly select representative genes in a protein interaction network. In line with this study, we performed high-throughput knockdown imaging screens for which cooperation partners developed a new automated method for large-scale tracking and classification of cell migration and proliferation (Harder et al., 2015).

Employing our methods, we investigated the regulation of the inflammato-ry response of immune cells in situ after bacterial and fungal infection lead-ing to a robust biomarker list which is consistent across several different datasets. In addition, we investigated aberrant regulatory mechanisms of metabolism in tumor cells and telomere maintenance mechanisms.

We set up a new method to estimate cell con-text specific regulation of transcription factors employing MILP on the transcriptome of the disease and compared this to the transcriptome of appropriate controls (Schacht et al., 2014). To elucidate disease specific regulation patterns in cellular networks, we applied Wavelet trans-forms on cellular pathways which we optimally arrange on two dimensional grids using MILP. This method was successfully applied to eluci-date regulatory patterns being responsible for longevity of Drosophila (Piro et al., 2014).

COLLABORATIONSAdebiyi, Ezekiel Covenant University, Ota, Nigeria

Bauer, Michael University Hospital Jena, Germany

Claus, Ralf University Hospital Jena, Germany

Giamarellos, Evangelios University of Athens, Greece

Kupiec, Martin University of Tel Aviv, Israel

Löffler, Jürgen Julius-Maximilians-Universität Würzburg, Germany

Luke, Brian Institute of Molecular Biology, Mainz, Germany

Platzer, Matthias Leibniz Institute on Aging – Fritz Lipmann Insti-tute, Jena, Germany

Pletz, Mathias University Hospital Jena, Germany

Rippe, Karsten German Cancer Research Center, Heidelberg, Germany

Slevogt, Hortense University Hospital Jena, Germany

ASSOCIATED GROUP NETWORK MODELING


SYSTEMIC INFECTIONS CAN CAUSE UNCONTROLLED IMMUNE RESPONSE FOLLOWED BY MULTIPLE ORGAN FAILURE LEADING TO SEPSIS.

OUR MISSION IS TO UNDERSTAND THE MOLECULAR CONTEXT TO IDENTIFY BIOMARKERS FOR EARLY DIAGNOSIS, DRUG TARGETS FOR THERAPY, AND

SUPPORTIVE MEASUREMENTS, ALSO FOR LONG TERM SEQUELAE.

Rainer König

SELECTED PUBLICATIONSPiro R, Wiesberg S, Oswald M, Eils R, König R (2014) Network topology-based detection of dif-ferential gene regulation and regulatory switch-es in cell metabolism and signaling. BMC Syst Biol 8, 56.

Schacht T, Oswald M, Eils R, Eichmüller S, König R (2014) Estimating the activity of transcription factors by the effect on their target genes. Bioin-formatics 30, i401-7.

Suratanee A, Schaefer MH, Betts MJ, Soons Z, Mannsperger H, Harder N, Oswald M, Gipp M, Ramminger E, Marcus G, Männer R, Rohr K, Wanker E, Russell RB, Andrade-Navarro MA, Eils R, König R (2014) Characterizing protein interac-tions employing a genome-wide siRNA cellular pheno-typing screen. PLOS Comput Biol 10(9), e1003814.

Harder N, Batra R, Diessl N, Gogolin S, Eils R, Westermann F, König R, Rohr K (2015) Large-scale tracking and classification for automatic analysis of cell migration and proliferation, and experimental optimization of high-throughput screens of neuroblastoma cells. Cytometry A 87A, 524-540.

Ummanni R, Mannsperger HA, Oswald M, Shar-ma, AK, König R, Korf U (2014) Evaluation of reverse phase protein array (RPPA)-based path-way-activation profiling in 84 non-small cell lung cancer (NSCLC) cell lines as platform for cancer proteomics and biomarker discovery. Biochim Biophys Acta 1844, 950-959.

MAJOR THIRD PARTY FUNDINGBMBF Integrated Research and Treatment Cen-ters Center for Sepsis Control and Care (CSCC)

– Systems biology of sepsis

BMBF Initiative eMed – Modeling telomere maintenance mechanisms networks in tumors

BMBF Initiative Cancer-SYS – Analyzing gene regulatory networks in neuro- ectodermal tumors

BMBF Initiative e:Bio – Innovation Competition Systems Biology – Analyzing the regulation of metabolic transformation in breast cancer

ASSOCIATED GROUP PHARMACEUTICAL MICROBIOLOGY

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The phenomenon of particularly secured biosyn-thetic steps in basidiomycetes by redundantly encoded enzymes was shown for involutin biosynthesis in Paxillus involutus (roll-rim mush-room) and for melleolide modification in Armil-laria mellea (honey mushroom). In the former case, three functionally equivalent quinone syn-thetases warrant the supply with the precursor atromentin. In the case of the honey mushroom, five flavin-dependent halogenases were found to catalyze regioselective chlorination of the ar-omatic moiety of the melleolides.

The research program on melleolide antibiotics was continued. A refined structure-activity re-lationship was established and a key structural feature for antifungal activity was identified. Fur-ther, very rapid cell death of human cancer cells and monocytes after melleolide treatment was discovered.

From a taxonomically undescribed stereaceous basidiomycete, two new branched-chain polyun-saturated fatty acid-like polyenes were isolated and their structure elucidated. These polyenes are also remarkable in that their production is induced by wounding of the mycelium and that

they are strongly active against insect larvae. Thus, these compounds likely represent a chem-ical defense mechanism.

The product of a cluster of natural product genes in Aspergillus fumigatus (the ftp locus) around a putative bimodular peptide synthetase gene was unknown. Combined genetic and biochem-ical research, in conjunction with chemical analysis, identified fumaryl-L-tyrosine and fuma-ryl-L-phenylalanine as small molecule products.

COLLABORATIONSKeller, Nancy P. University of Wisconsin-Madison, USA

Tunlid, Anders University of Lund, Sweden

Werz, Oliver Friedrich Schiller University Jena, Germany

ASSOCIATED GROUPPHARMACEUTICAL MICROBIOLOGY


SELECTED PUBLICATIONSBohnert M, Nützmann HW, Schroeckh V, Horn F, Dahse HM, Brakhage AA, Hoffmeister D (2014) Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure activity re-lationships. Phytochemistry 105, 101-108.

Schwenk D, Nett M, Dahse HM, Horn U, Blanch-ette R, Hoffmeister D (2014) Injury-induced bio-synthesis of branched-chain polyene pigments in a white-rotting basidiomycete. J Nat Prod 77, 2658-2663.

Kalb D, Heinekamp T, Lackner G, Scharf D, Dahse HM, Brakhage AA, Hoffmeister D (2015) Genetic engineering activates biosynthesis of aromatic fumaric acid amides in the human pathogen Aspergillus fumigatus. Appl Environ Microbiol 81, 1594-1600.

Braesel J, Götze S, Shah F, Heine D, Tauber J, Hertweck C, Tunlid A, Stallforth P, Hoffmeister D (2015) Three redundant synthetases secure re-dox-active pigment production in the basidiomy-cete Paxillus involutus. Chem Biol 22, 1325-1334.

WE FOCUS ON FUNGAL AND BACTERIAL NATURAL PRODUCTS AS POTENTIAL NEW PHARMACEUTICALS OR AS CHEMICAL

SIGNALS IN MICROBIAL COMMUNICATION. WE ELUCIDATE THE BIOCHEMICAL AND GENETIC BASIS OF THEIR BIOSYNTHESES,

EMPHASIZING BASIDIOMYCETE SECONDARY METABOLISM.

Dirk Hoffmeister

Wick J, Heine D, Lackner G, Misiek M, Tauber J, Jagusch H, Hertweck C, Hoffmeister D (2015) A fivefold parallelized biosynthetic process se-cures chlorination of Armillaria mellea (honey mushroom) toxins. Appl Environ Microbiol 82, 1196-1204.

MAJOR THIRD PARTY FUNDINGDFG Project – Deciphering the substrate spec-ificity code of basidiomycete peptide synthe-tases

Figure: Carpophores of the Crimson Waxy Cap Hygrocybe punicea, a basidiomycete of open grasslands.

FACTS AND FIGURES

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ORGANIZATION OF THE HKIORGANISATION DES HKI


Board of Trustees | Kuratorium

Dr. Bernd Ebersold Thuringian Ministry of Economy, Science and the Digital Society (Head)

Nikolaus Graf zu Stolberg Medac GmbH, Wedel (Deputy Head)

Prof. Dr. Gabriele Diekert Friedrich Schiller University Jena

Prof. Dr. Thorsten Heinzel Vice-Rector of Friedrich Schiller University Jena

Dr. Matthias Kölbel Federal Ministry of Education and Research, Berlin (since 15.06.2015)

Prof. Dr. Frank Laplace Federal Ministry of Education and Research, Berlin (until 12.10.2014)

Dr. Thomas Maier Wacker Biotech Jena GmbH

PD Dr. Klaus-Peter Michel Federal Ministry of Education and Research, Berlin (13.10.2014–14.06.2015)

Prof. Dr. Walter Rosenthal Max Delbrück Center for Molecular Medicine, Berlin,since 01.09.2014 Friedrich Schiller University Jena

Scientific Advisory Board | Wissenschaftlicher Beirat

Prof. Dr. Walter Rosenthal Max Delbrück Center for Molecular Medicine, Berlin,since 01.09.2014 Friedrich Schiller University Jena (Head)

Prof. Dr. Gabriele Diekert Friedrich Schiller University Jena (Deputy Head)

Prof. Dr. Elke Dittmann University Potsdam

Prof. Dr. Bernhard Fleischer Bernhard Nocht Institute for Tropical Medicine, Hamburg

Prof. Dr. Hubertus Haas Innsbruck Medical University

Prof. Dr. Jörg Hacker German National Academy of Sciences Leopoldina, Halle (Saale)

Prof. Dr. Peter Neubauer Technical University Berlin

Prof. Dr. Georg Pohnert Friedrich Schiller University Jena

Prof. Dr. Joachim Selbig University Potsdam

Executive Board | Vorstand

Prof. Dr. Axel A. Brakhage Scientific director

Elke Jäcksch Administrative director

Scientific Coordination | Wissenschaftliche Koordination

Dr. Michael Ramm Head

Dr. Christine Vogler Deputy head

Angelika Rauchmaul

Administration | Verwaltung

Elke Jäcksch Administrative director

Renate Becher // Sandra Ertel // Fabian Grunert (until 08/2015) // Nils Haußner // Eckhard Hemme // Carmen HenzeMichael Hetz // Britta Kammer-Rattey // Michael Kind // Jan Kösling-Wettstaedt // Stefan Liebert (since 07/2014)Ilona Lux // Andrea Matthies // Frank Schebitz // Reinald Schorcht // Michael Schunk // Kerstin Seiler (since 11/2015)Christine Serfling // Kerstin Siegmund // Ekkehard Tittelbach // Jens Trotzer

122

Besides original publications in peer-reviewed journals, intellectual property rights are an important perfor-mance parameter for research work at the HKI. Re-search teams from the main research fields of the HKI, natural product research and infection biology, as well as technology-oriented groups contributed a number of inventions to the institute‘s IP portfolio in 2014/2015. Patents applied for by the HKI have led to a number of fruitful industrial cooperations and form the basis for application-oriented third-party funding projects.

Christian Hertweck and his team from the Department of Biomolecular Chemistry have investigated a bacte-rium that is normally oxygen-sensitive and mainly in-fects potatoes. The results showed quite unexpectedly that this anaerobic bacterium called Clostridium puni-ceum is able to survive in an oxygen-containing envi-ronment. While studying the molecular mechanism of this oxygen protection, the team came across a group of substances called clostrubins that enable them to live in an oxygen-rich environment. Particularly sur-prising was that the clostrubins also have a strong antibiotic effect. The dual function of the clostrubin is new and reveals an unknown strategy of plant patho-gens. The aim of further research is now to develop the clostrubins into lead structures for new antibiotics for human medicine.

Markus Nett, head of the junior research group Sec-ondary Metabolism of Predatory Bacteria, and his team discovered a new, highly potent antibiotic. It could potentially be used to treat hospital-acquired in-fections. While most bacteria feed on dead substrates, a few have learned to use their own kind as a source of food. These predatory bacteria produce antibiotics to kill their prey. Markus Nett‘s group at the HKI is dedi-cated to this field. They isolated a predatory bacterium called Pyxidicoccus fallax from the bank mud of the river Saale. The strain produces antibiotics that are highly effective against multi-resistant Gram-positive bacteria without harming human or animal cells.

These exceptionally potent antibiotics, known as gulmirecins, are not only found in Jena. At the same time, researchers led by Rolf Müller of the Helmholtz Institute for Pharmaceutical Research of the Saarland (HIPS) discovered similar active substances in other predatory bacteria. Both groups have jointly applied for a patent on the substances and are working on their further research.

The application for new intellectual property rights is subject to strict in-house evaluation and focuses on new, biologically active natural substances and their (bio-)synthetic derivatives as well as promising targets for the diagnosis and therapy of infectious diseases.

ERFINDUNGEN UND SCHUTZRECHTE

Schutzrechte sind neben Originalpublikationen in refe-rierten Fachjournalen ein wesentlicher Leistungspara-meter für die Forschungsarbeit am HKI. Forschungs-teams aus den Hauptforschungsfeldern des HKI, Naturstoff-Forschung und Infektionsbiologie, trugen ebenso wie Technologie-orientierte Gruppen im Zeit-raum 2014/2015 mit einer Reihe von Erfindungen zum Schutzrechts-Portfolio des Instituts bei. Vom HKI an-gemeldete Patente führten zu einer Reihe fruchtbarer Industriekooperationen und bilden die Grundlage für anwendungsorientierte Drittmittelvorhaben.

Christian Hertweck und sein Team aus der Abteilung Biomolekulare Chemie hat ein normalerweise Sau-erstoff-empfindliches Bakterium untersucht, das vor allem Kartoffeln befällt. Die Ergebnisse zeigten völlig unerwartet, dass dieses Bakterium mit dem Namen Clostridium puniceum in der Lage ist, in Umgebung mit

INVENTIONS AND PATENTS 2014/2015

Gulmirecin


Sauerstoff dennoch zu überleben. Beim Studium des molekularen Mechanismus dieses Sauerstoff-Schut-zes stieß das Team auf eine Gruppe von Wirkstoffen, die Clostrubine, die es ihm ermöglichen, in sauer-stoffreicher Umgebung zu leben. Überraschend war, dass die Clostrubine gleichzeitig eine stark antibio-tische Wirkung aufweisen. Die Doppelfunktion der Clostrubine ist neu und deckt eine neue Strategie von Krankheitserregern in Pflanzen auf. Ziel weiterer For-schungsarbeiten ist nun, die Clostrubine nach ihrer Anmeldung zum Patent zu Leitstrukturen für neue An-tibiotika für die Humanmedizin zu entwickeln.

Markus Nett, Leiter der Nachwuchsgruppe Sekundär-metabolismus räuberischer Bakterien, entdeckte mit seinem Team ein neues, hochpotentes Antibiotikum. Es könnte möglicherweise zur Behandlung von Kran-kenhausinfektionen eingesetzt werden. Während sich die meisten Bakterien von abgestorbenen Substraten ernähren, haben einige wenige gelernt, ihresgleichen als Nahrungsquelle zu nutzen. Um ihre Beute zu erle-gen, produzieren diese räuberisch lebenden Bakterien Antibiotika. Diesem Gebiet widmet sich die Gruppe um Markus Nett am HKI. Aus Uferschlamm der Saale iso-lierte sie ein räuberisches Bakterium mit dem Namen Pyxidicoccus fallax. Der Stamm produziert Antibiotika, die hochwirksam gegen multiresistente grampositive Bakterien sind, ohne menschlichen oder tierischen Zel-len zu schaden.

Die außergewöhnlich potenten Antibiotika, sie erhielten die Bezeichnung Gulmirecine, finden sich aber nicht nur in Jena. Zeitgleich haben Forscher um Rolf Müller vom Helmholtz-Institut für Pharmazeutische Forschung des Saarlandes (HIPS) ähnliche Wirkstoffe in anderen räuberischen Bakterien entdeckt. Gemeinsam haben beide Gruppen die Substanzen zum Patent angemeldet und arbeiten an deren weiterer Erforschung.

Die Anmeldung neuer Schutzrechte unterliegt einer strengen hausinternen Evaluation und konzentriert sich auf neue, biologisch aktive Naturstoffe und deren (bio-)synthetische Derivate sowie vielversprechende Targets für die Diagnose und Therapie von Infektions-krankheiten.

Pidot S, Ishida K, Shabuer G, Cyrulies M,Hertweck CClostrubinsPCT/EP2015/000162Priority date 2014-01-28

Surup F, Steinmetz H, Mohr K, Viehrig K,Müller R, Nett M, Schieferdecker S, Dahse HM,Wolling M, Kirschning ANovel macrolide antibioticsPCT/EP2015/001384Priority date 2014-07-07

Scheffold A, Bacher P, Kniemeyer O,Teutschbein J, Brakhage AImmunogenic antigens from Aspergillus fumigatusEP14181113.3Priority date 2014-08-15

Tovar M, Mahler L, Zang E, Roth MSystem zur Inkubation von mikrofluidischen Tropfen und Verfahren zur Bereitstellung von homogenen Inkubationsbedingungen in einer Tropfeninkubations-einheitDE201510106870Priority date 2014-11-10

Tovar M, Zang E, Weber TDevice and method for extracting individual picoliter droplets from microfluidic emulsions for further analysis and scale-up EP20150193893Priority date 2014-11-10

Brack-Werner R, Helfer M, Rösner M, Schneider M, Protzer U, Hertweck C, Werneburg MPyrone derivatives for use as antiviral agentsPCT/EP2016/057598Priority date 2015-04-10

Petzke L, Herold A, Fleck C, Dickhaut J, Brakhage A, Valiante V, Mattern DJ, Horn F, Guthke R, Linde J, Walther GGene cluster for biosynthesis of austinoidsPCT/IB2016/057403Priority date 2015-12-16

Clostrubin

124

404Scientific Talks given by HKI Employeesvon HKI-Mitarbeitern gehaltene wiss. Vorträge

70Scientific AwardsPreise und Auszeichnungen

59Memberships in Editorial BoardsMitgliedschaften in Editorial Boards

4Calls for AppointmentsRufe auf Professuren

73Bachelor and Master DegreesBachelor- / Masterabschlüsse

45GraduationsPromotionen 328

PublicationsPublikationen

283Thereof Original Publicationsdavon Originalpublikationen

HKI AT A GLANCE DAS HKI AUF EINEN BLICK


7Inventions and PatentsPatente und Schutzrechte

Media ReportsMedienberichte

44 Print

15 TV and Radio

22Scientific ColloquiaWissenschaftliche Kolloquien

402StaffMitarbeiter (Stand 31.12.2015)

11,5 Mio EuroExternal FundingDrittmittel

28Participation in Research NetworksNetzwerke und Verbundprojekte

13Organization of Symposia and ConferencesOrganisation von Tagungen und Konferenzen

126

EXTERNAL FUNDING 2014/2015 DRITTMITTEL

Participation in Research Networks |Beteiligung an Netzwerken undVerbundprojekten

EU

EURenOmics: European Consortium for High-Throughput Research in Rare Kidney Diseases (Large-scale integrating project) Duration: 2012-2017 PI: Zipfel, Peter F. Total funding: 150,000 € Funding 2014/15: 100,000 €

QuantFung – Discovery of Streptomyce-tes induced fungal secondary metabolite formation (Marie Curie Initial Training Network (ITN)) Duration: 2013-2017 PI: Brakhage, Axel Total funding: 238,000 € Funding 2014/15: 131,000 €

Leibniz Association

KAIT: Kryostress - Anpassungsmechanis-men der Zelle an Tiefstemperaturen (Leibniz Competition) Duration: 2013-2017 PI: Kniemeyer, Olaf Total funding: 154,500 € Funding 2014/2015: 103,000 €

Leibniz ScienceCampus InfectoOptics: Com-bating infectious diseases with advanced optical methods (Leibniz ScienceCampus) Duration: 2015-2018 PIs: Brakhage, Axel (spokesperson); Figge,Marc Thilo; Horn, Uwe; Hube, Bernhard; Jacobsen, Ilse; Kurzai, Oliver Total funding: 386,219 € Funding 2014/2015: 32,229 €

MikrOMIC: Die Rolle von Mikroplastik als Trä-ger mikrobieller Populationen im Ökosystem Ostsee (Leibniz Competition) Duration: 2014-2017 PI: Hillmann, Falk Total funding: 6,500 € Funding 2014/15: 3,700 €

DFG

SPP 1580: Intracellular compartments as places of pathogen-host-interactions (Priority Programme) Duration: 2011-2017 PI: Hube, Bernhard Total funding: 296,950 € Funding 2014/15: 132,000 €

CRC 1127 ChemBioSys: Chemical Mediators in Complex Biosystems (Collaborative Research Center) Duration: 2014-2018 PIs: Hertweck, Christian (spokesperson);Brakhage, Axel; Nett, Markus; Guthke, Rein-hard; Shelest, Ekaterina Total funding: 1,397,000 € Funding 2014/2015: 485,000 €

GSC 214 JSMC: Jena School for Microbial Communication (Graduate School of Excellence) Duration: 2007-2017 PIs: Brakhage, Axel (spokesperson); Beemel-manns, Christine; Brock, Matthias; Figge, Marc Thilo; Guthke, Reinhard; Hertweck, Christian; Hillmann, Falk; Horn, Uwe; Hube, Bernhard; Jacobsen, Ilse; König, Rainer; Kurzai, Oliver; Saluz, Hans Peter; Shelest, Ekaterina; Stallforth, Pierre; Zipfel, Peter F. Total funding: 4,4323,000 € Funding 2014/2015: 1,329,000 €

CRC/TR 124 FungiNet: Pathogenic fungi and their human host: Networksof Interaction (Collaborative Research Center / Transregio) Duration: 2013-2017 PIs: Brakhage, Axel (spokesperson), Figge, Marc Thilo; Guthke, Reinhard Hube,

Bernhard; Jacobsen, Ilse; Kniemeyer, Olaf; Shelest, Ekaterina; Skerka, Christine; Voigt, Kerstin; Zipfel, Peter F. Total funding: 3,114,000 € Funding 2014/2015: 1,691,000 €

JIMI: Joint Intravital Microscopy and Imaging platform –a network for intravital microscopy Duration: 2012-2015 PI: Figge, Marc Thilo Total funding: 219,000 € Funding 2014/2015: 116,000 €

BMBF

Cancer-SYS – Analyzing gene regulatory networks in neuro- ectodermal tumors Duration: 2013-2016 PI: König, Rainer Total funding: 227,000 € Funding 2014/2015: 146,000 €

e:Bio – Innovation Competition Systems Biology – Analyzing the regulation of meta-bolic transformation in breast cancer Duration: 2013-2015 PI: König, Rainer Total funding: 227,000 € Funding 2014/2015: 147,000 €

FunComPath: Fungal Commensal-to- Pathogenicity (ERA-Net Infect-ERA) Duration: 2015-2018 PI: Hube, Bernhard Total funding: 264,000 € Funding 2014/2015: 59,000 €

GERONTOSYS: Systems biology for healthy aging Duration: 2011-2014 PI: Guthke, Reinhard Total funding: 191,000 € Funding 2014/2015: 13,000 €


InfectControl 2020: New antiinfection strate-gies – Science • Society • Economy (Zwanzig20 – Partnerschaft für Innovation) Duration: 2014-2020 PIs: Brakhage, Axel (spokesperson);Kurzai, Oliver; Nett, Markus; Kniemeyer, Olaf; Guthke, Reinhard; Hertweck, Christian; Kloß, Florian Total funding: 4,876,000 € Funding 2014/2015: 1,372,000 €

InfectoGnostics Research Campus Duration: 2015-2020 PIs: Jacobsen, Ilse Total funding: 590,500 € Funding 2014/2015: 55,000 €

CSCC: Integrated Research and Treatment Centers Center for Sepsis Control and Care Duration: 2011-2020 PIs: Brakhage, Axel; Kurzai, Oliver; Kniemey-er, Olaf; Jacobsen, Ilse; Hube, Bernhard; Zipfel, Peter F. Total Funding: 1,621,000 € Funding 2014/2015: 357,000 €

LRC: Leibniz Research Cluster Bio/synthetic multifunctional micro production units – novel ways of compound development (Strategy Process Biotechnology 2020+) Duration: 2015-2020 PIs: Brakhage, Axel (spokesperson); Valiante, Vito Total funding: 1,502,000 € Funding 2014/2015: 202,000 €

PathoGenoMics: Trans-European coopera-tion and coordination of genome sequencing and functional genomics of human-patho-genic microorganisms (ERA-NET PathoGenoMics) 2011– 2014 PIs: Brakhage, Axel; Hube, Bernhard Total funding: 472,000 € Funding 2014/2015: 45,000 €

SPICE III: Einfluss von Meeresverschmut-zung auf Biodiversität und den Lebensunter-halt von Küstenbewohnern

(Wissenschaftlich-Technische Zusammen-arbeit mit Indonesien) Duration: 2012-2016 PI: Saluz, Hans Peter Total funding: 297,000 € Funding 2014/2015: 132,000 €

Virtual Liver Duration: 2010-2015 PI: Guthke, Reinhard Total funding: 312,000 € Funding 2014/2015: 135,000 €

BMG/RKI

NRZMyk: National Reference Center for Invasive Mycoses Duration: 2014-2019 PIs: Kurzai, Oliver; von Lilienfeld-Toal, Marie; Voigt, Kerstin Total funding: 474,000 € Funding 2014/2015: 156,000 €

Free State of Thuringia

DropCode: Microfluidic platform technology for ultra-high throughput screening of novel antimicrobial compounds from microorgan-isms (Thüringen GreenTech) Duration: 2014-2016 PIs: Figge, Marc Thilo; Roth, Martin Total funding: 195,000 € Funding 2014/2015: 146,000 €

DZIF

New natural compounds Duration: 2013-2015 PIs: Roth, Martin Total funding: 216,000 € Funding 2014/2015: 168,000 €

BTZ043 a novel TB drug Duration: 2015-2016 PI: Voigt, Kerstin Total funding: 36,000 € Funding 2014/2015: 18,000 €

Leibniz Research Alliances

Bioactive Compounds and BiotechnologyHealth TechnologiesInfections’21: Transmission Control of Infec-tions in the 21th Century

Individual Projects | Einzelvorhaben

BMBF

Gene silencing in human pathogeniczygomycetes (Collaboration with Hungary) Duration: 2014-2016 PI: Voigt, Kerstin Total funding: 16,500 € Funding 2014/2015: 7,000 €

BMWi

OptiMikroL: Optisches Detektionssystem für den Sofortnachweis von Mikroorganismen in Lebensmittelproduktionsmaschinen (The Central Innovation Programme for SMEs) Duration: 2014-2016 PI: Saluz, Hans Peter Total funding: 87,500 € Funding 2014/2015: 73,000 €

DFG

Rolle der Komplementregulatoren Faktor H, FHL1, CFHR1 und CFHR3 bei der Alters-abhängigen Makuladegeneration (AMD) des Auges (Research Grant) Duration: 2012-2015 PI: Skerka, Christine Total funding: 281,000 € Funding 2014/2015: 175,000 €

CO2 Adaption in Candida glabrata and itsrole in host-pathogen interaction (Research Grant) Duration: 2013-2017 PI: Kurzai, Oliver Total funding: 187,500 € Funding 2014/2015: 94,000 €

128

Deciphering the substrate specificity code of basidiomycete peptide synthetases (Research Grant) Duration: 2014-2017 PI: Hoffmeister, Dirk Total funding: 187,600 € Funding 2014/2015: 70,000 €

Gottfried Wilhelm Leibniz Prize PI: Hertweck, Christian Total funding: 3,000,000 €

Identifizierung und Analyse von Chlamy-dosporen- und Pathogenitäts-assoziierten Genen in Candida albicans (Research Grant) Duration: 2010-2014 PI: Hube, Bernhard Total funding: 106,000 € Funding 2014/2015: 46,000 €

Microevolution of pathogenic yeasts during interactions with the host immune system (D-A-CH Lead Agency Action) Duration: 2011-2016 PI: Hube, Bernhard Total funding: 280,000 € Funding 2014/2015: 147,000 €

MorphPath: The Role of morphogenesis in the pathogenesis of systemic candidiasis (Research Grant) Duration: 2013-2016 PI: Jacobsen, Ilse Total funding: 192,000 € Funding 2014/2015: 101,000 €

Novel molecular mechanismsof iron sensing and homeostasis in filamentous fungi (D-A-CH Lead Agency Action) Duration: 2014-2017 PIs: Brakhage, Axel; Hortschansky, Peter Total funding: 366,000 € Funding 2014/2015: 165,000 €

Polyphasic taxonomic revision ofMucoraceae (Research Grant) Duration: since 2014 PI: Walther, Grit Total funding: 159,000 € Funding 2014/2015:53,000 €

Other sources

Aventis FoundationThe Roles of Eukaryotic Polyketides in Interspecies Interactions of Dictyostelium discoideum Duration: 2015-2017 PI: Stallforth, Pierre Total funding: 49,000 € Funding 2014/2015: 6,000 €

Daimler and Benz FoundationDeciphering the Chemical Communication Code in Symbiotic Eukaryote-Prokaryote Interactions (Postdoc Fellowship) Duration: 2014-2016 PI: Stallforth, Pierre Total funding: 40,000 € Funding 2014/2015: 38,000 €

Exploring the Chemical Potential ofTermite-associated Bacteria (Postdoc Fellowship) Duration: 2014-2016 PI: Beemelmanns, Christine Total funding: 40,000 € Funding 2014/2015: 38,000 €

Deutsche Jose Carreras-LeukämiestiftungRespiratory viruses in patients afterallogeneic stem cell transplantation Duration: 2015-2016 PI: von Lilienfeld-Toal, Marie Total funding: 15,000 €Funding 2014/2015: 5,000 €


STAFF MITARBEITER

12ProfessorsProfessoren

7Group LeadersGruppenleiter

102Doctoral ResearchersDoktoranden

33Bachelor and Master StudentsBacheloranden und Masteranden

77Non-scientific EmployeesNichtwissenschaftliches Personal54 %

Female EmployeesFrauenanteil

30 %International EmployeesInternationale Mitarbeiter

7TraineesAuszubildende

86Research Associates Wissenschaftliche Mitarbeiter

Status 31.12.2015

130

PEER REVIEWED ARTICLESORIGINALARBEITEN

Department Biomolecular Chemistry

Cai X, Ng K, Panesar H, Moon SJ, Paredes M, Ishida K, Hertweck C, Minehan TG (2014) Total synthesis of the antitumor natural product polycarcin V and evaluation of its DNA binding profile. Org Lett 16, 2962-2965.

Chankhamjon P, Boettger-Schmidt D, Scherlach K, Urbansky B, Lackner G, Kalb D, Dahse HM, Hoffmeister D, Hertweck C (2014) Biosynthesis of the halogenated my-cotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion. Angew Chem Int Ed 53, 13409-13413.

Coyne S, Litomska A, Chizzali C, Khalil MN, Richter K, Beerhues L, Hertweck C (2014) Control of plant defense mechanisms and fire blight pathogenesis through the regula-tion of 6-thioguanine biosynthesis in Erwinia amylovora. Chembiochem 15, 373-376.

Franke J, Ishida K, Hertweck C (2014) Evolution of siderophore pathways in human pathogenic bacteria. J Am Chem Soc 136, 5599-5602

Gatte-Picchi D, Weiz A, Ishida K, Hertweck C, Dittmann E (2014) Functional analysis of environmental DNA-derived microviridins provides new insights into the diversity of the tricyclic peptide family. Appl Environ Microbiol 80, 1380-1387.

Habel A, Scharf DH, Heinekamp T, Brakhage AA, Hertweck C (2014) Opposed effects of enzymatic gliotoxin N-and S-methylations. J Am Chem Soc 136, 11674-11679.

Haq IU, Graupner K, Nazir R, van Elsas JD (2014) The genome of the fungal-interactive soil bacterium Burkholderia terrae BS001-a plethora of outstanding interactive capabili-ties unveiled. Genome Biol Evol 6, 1652-1668.

Heine D, Bretschneider T, Sundaram S, Hertweck C (2014) Enzymatic polyketide chain branching to give substituted lactone, lactam, and glutarimide heterocycles. Angew Chem Int Ed 53, 11645-11649.

Heine D, Martin K, Hertweck C (2014) Genomics-guided discovery of en-dophenazines from Kitasatospora sp. HKI 714. J Nat Prod 77, 1083-1087.

Hölscher D, Dhakshinamoorthy S, Alexan-drov T, Becker M, Bretschneider T, Buerkert A, Crecelius AC, De Waele D, Elsen A, Heckel DG, Heklau H, Hertweck C, Kai M, Knop K, Krafft C, Maddula RK, Matthäus C, Popp J, Schneider B, Schubert US, Sikora RA, Svatoš A, Swennen RL (2014) Phenalenone-type phytoalexins mediate resistance of banana plants (Musa spp.) to the burrowing nema-tode Radopholus similis. Proc Natl Acad Sci 111, 105-110.

Jaschinski T, Helfrich EJ, Bock C, Wolfram S, Svatoš A, Hertweck C, Pohnert G (2014) Matrix-free single-cell LDI-MS investigations of the diatoms Coscinodiscus granii and Thalassiosira pseudonana. J Mass Spectrom 49, 136-144.

Kloss F, Chiriac AI, Hertweck C (2014) Map-ping of the modular closthioamide architec-ture reveals crucial motifs of polythioamide antibiotics. Chemistry 20, 15451-15458.

Letzel AC, Pidot SJ, Hertweck C (2014) Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria. BMC Genom-ics 15, 983.

Moebius N, Uzüm Z, Dijksterhuis J, Lackner G, Hertweck C (2014) Active invasion of bac-teria into living fungal cells. eLife 2, e03007.

Mohan S, Hertweck C, Dudda A, Hammer-schmidt S, Skerka C, Hallström T, Zipfel PF (2014) Tuf of Streptococcus pneumoniae is a surface displayed human complement regulator binding protein. Mol Immunol 62, 249-264.

Pidot S, Ishida K, Cyrulies M, Hertweck C (2014) Discovery of clostrubin, an exception-al polyphenolic polyketide antibiotic from a strictly anaerobic bacterium. Angew Chem Int Ed 53, 7856-7859.

Pidot SJ, Coyne S, Kloss F, Hertweck C (2014) Antibiotics from neglected bacterial sources. Int J Med Microbiol 304, 14-22.

Ross C, Opel V, Scherlach K, Hertweck C (2014) Biosynthesis of antifungal and antibacterial polyketides by Burkholderia gladioli in coculture with Rhizopus microspo-rus. Mycoses 57, 48-55.

Ross C, Scherlach K, Kloss F, Hertweck C (2014) The molecular basis of conjugated polyyne biosynthesis in phytopathogenic bacteria. Angew Chem Int Ed 53, 7794-7798.

Scharf DH, Groll M, Habel A, Heinekamp T, Hertweck C, Brakhage AA, Huber EM (2014) Flavoenzyme-catalyzed formation of disul-fide bonds in natural products. Angew Chem Int Ed 53, 2221-2224.

Scharf DH, Habel A, Heinekamp T, Brakhage AA, Hertweck C (2014) Opposed effects of enzymatic gliotoxin N- and S-methylations. J Am Chem Soc 136, 11674-11679.

Sugimoto Y, Ding L, Ishida K, Hertweck C (2014) Rational design of modular polyketide synthases: morphing the aureothin pathway into a luteoreticulin assembly line. Angew Chem Int Ed 53, 1560-1564.

Sun Y, Chen P, Zhang D, Baunach M, Hertweck C, Li A (2014) Bioinspired total synthesis of sespenine. Angew Chem Int Ed 53, 9012-9016.

Weiz AR, Ishida K, Quitterer F, Meyer S, Kehr JC, Müller KM, Groll M, Hertweck C, Ditt-mann E (2014) Harnessing the evolvability of tricyclic microviridins to dissect protease-in-hibitor interactions. Angew Chem Int Ed 53, 3735-3738.

Xu Z, Baunach M, Ding L, Peng H, Franke J, Hertweck C (2014) Biosynthetic code for di-vergolide assembly in a bacterial mangrove endophyte. ChemBioChem 15, 1274-1279.

Zaehle C, Gressler M, Shelest E, Geib E, Hertweck C, Brock M (2014) Terrein biosyn-thesis in Aspergillus terreus and its impact on phytotoxicity. Chem Biol 21, 719-731.


Barnes EC, Bezerra-Gomes P, Nett M, Hertweck C (2015) Dandamycin and chan-drananimycin E, benzoxazines from Strepto-myces griseus. J Antibiot 68, 463-468.

Baunach M, Ding L, Willing K, Hertweck C (2015) Bacterial synthesis of unusual sulfonamide and sulfone antibiotics by fla-voenzyme-mediated sulfur dioxide capture. Angew Chem Int Ed 54, 13279-13283.

Baunach M, Franke J, Hertweck C (2015) Terpenoid biosynthesis off the beaten track: unconventional cyclases and their impact on biomimetic synthesis. Angew Chem Int Ed 54, 2604-2626.

Braesel J, Götze S, Shah F, Heine D, Tauber J, Hertweck C, Tunlid A, Stallforth P, Hoffmeis-ter D (2015) Three redundant synthetases secure redox-active pigment production in the basidiomycete Paxillus involutus. Chem Biol 22, 1325-1334.

Chiriac AI, Kloss F, Krämer J, Vuong C, Hertweck C, Sahl HG (2015) Mode of action of closthioamide: the first member of the polythioamide class of bacterial DNA gyrase inhibitors. J Antimicrob Chemother 70, 2576-2588.

Ding L, Franke J, Hertweck C (2015) Divergolide congeners illuminate alternative reaction channels for ansamycin diversifica-tion. Org Biomol Chem 13, 1618-1623.

Ding L, Goerls H, Dornblut K, Lin W, Maier A, Fiebig HH, Hertweck C (2015) Bacaryolanes A-C, rare bacterial caryolanes from a man-grove endophyte. J Nat Prod 78, 2963-2967.

Franke J, Ishida K, Hertweck C (2015) Plasticity of the malleobactin pathway and its impact on siderophore action in human pathogenic bacteria. Chemistry 21, 8010-8014.

Graupner K, Lackner G, Hertweck C (2015) Genome sequence of mushroom soft-rot pathogen Janthinobacterium agaricidamno-sum. Genome Announc. 3, pii: e00277-15.

Gressler M, Meyer F, Heine D, Hortschansky P, Hertweck C, Brock M (2015) Phytotoxin production in Aspergillus terreus is regulated by independent environmental signals. eLife 4, e07861.

Heine D, Sundaram S, Bretschneider T, Hert- weck C (2015) Twofold polyketide branching

by a stereoselective enzymatic Michael addition. Chem Commun 51, 9872-9875.

Horn F, Habel A, Scharf DH, Dworschak J, Brakhage AA, Guthke R, Hertweck C, Linde J (2015) Draft genome sequence and gene annotation of the entomopathogenic fungus Verticillium hemipterigenum. Genome Announc 3, e01439-14.

Horn F, Üzüm Z, Möbius N, Guthke R, Linde J, Hertweck C (2015) Draft genome se-quences of symbiotic and nonsymbiotic Rhi-zopus microsporus strains CBS 344.29 and ATCC 62417. Genome Announc 3, e01370-14.

Korp J, König S, Schieferdecker S, Dahse HM, König GM, Werz O, Nett M (2015) Harnessing enzymatic promiscuity in myxochelin biosynthesis for the production of 5-lipoxygenase inhibitors. ChemBioChem 16, 2445-2450.

Leonhardt I, Spielberg S, Weber M, Albrecht- Eckardt D, Bläss M, Claus R, Barz D, Scher-lach K, Hertweck C, Löffler J, Hünniger K, Kurzai O (2015) The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immu-nity. mBio 6, e00143.

Liaimer A, Helfrich EJ, Hinrichs K, Guljamow A, Ishida K, Hertweck C, Dittmann E (2015) Nostopeptolide plays a governing role during cellular differentiation of the symbiotic cya-nobacterium Nostoc punctiforme. Proc Natl Acad Sci 112, 1862-1867.

Macheleidt J, Scherlach K, Neuwirth T, Schmidt-Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Hert-weck C, Heinekamp T, Brakhage AA (2015) Transcriptome analysis of cAMP-dependent protein kinase A regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus. Mol Microbiol 96, 148-162.

Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Mo-rales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escriba-no JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ,

Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O‘Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11, 625-631.

Shabuer G, Ishida K, Pidot SJ, Roth M, Dahse HM, Hertweck C (2015) Plant pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory. Science 350, 670-674.

Sugimoto Y, Ishida K, Traitcheva N, Busch B, Dahse HM, Hertweck C (2015) Freedom and constraint in engineered noncolinear polyketide assembly lines. Chem Biol 22, 229-240.

Sundaram S, Heine D, Hertweck C (2015) Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching. Nat Chem Biol. 11, 949-951.

Üzüm Z, Silipo A, Lackner G, De Felice A, Molinaro A, Hertweck C (2015) Structure, ge-netics and gunction of an exopolysaccharide produced by a bacterium living within fungal hyphae. ChemBioChem 16, 387-392.

Zocher G, Vilstrup J, Heine D, Hallab A, Goralski E, Hertweck C, Stahl M, Schäberle TF, Stehle T (2015) Structural basis of head to head polyketide fusion by CorB. Chem Sci 6, 6525-6536.

132

Department Infection Biology

Barthel A, Kopka I, Vogel H, Zipfel PF, Heckel DG, Groot AT (2014) Immune defence strategies of generalist and specialist insect herbivores. Proc Biol Sci 281, 20140897.

Bernhard S, Fleury C, Su YC, Zipfel PF, Koske I, Nordström T, Riesbeck K (2014) Outer membrane protein olpA contributes to Moraxella catarrhalis serum resistance via interaction with factor H and the alternative pathway. J Infect Dis 210, 1306-1310.

Bohnert M, Nützmann HW, Schroeckh V, Horn F, Dahse HM, Brakhage AA, Hoff-meister D (2014) Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure-activity relationships. Phytochemistry 105, 101-108.

Bohnert M, Scherer O, Wiechmann K, König S, Dahse HM, Hoffmeister D, Werz O (2014) Melleolides induce rapid cell death in human primary monocytes and cancer cells. Bioorg Med Chem 22, 3856-3861.

Chankhamjon P, Boettger-Schmidt D, Scherlach K, Urbansky B, Lackner G, Kalb D, Dahse HM, Hoffmeister D, Hertweck C (2014) Biosynthesis of the halogenated my-cotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion. Angew Chem Int Ed 53, 13409-13413.

Chen Q, Wiesener M, Eberhardt HU, Hart-mann A, Uzonyi B, Kirschfink M, Amann K, Buettner M, Goodship T, Hugo C, Skerka C, Zipfel PF (2014) Complement factor H-relat-ed hybrid protein deregulates complement in dense deposit disease. J Clin Invest 124, 145-155

Fleury C, Su YC, Hallström T, Sandblad L, Zipfel PF, Riesbeck K (2014) Identification of a Haemophilus influenzae factor H-binding lipoprotein involved in serum resistance. J Immunol 192, 5913-5923.

Hammerschmidt C, Koenigs A, Siegel C, Hallström T, Skerka C, Wallich R, Zipfel PF, Kraiczy P (2014) Versatile roles of CspA orthologs in complement inactivation of serum-resistant Lyme disease spirochetes. Infect Immun 82, 380-392.

Kirchhoff KN, Klingelhöfer I, Dahse HM, Morlock G, Wilke T (2014) Maturity-related changes in venom toxicity of the freshwater stingray Potamotrygon leopoldi. Toxicon 92, 97-101.

Kraibooj K*, Park HR*, Dahse HM, Skerka C, Voigt K+, Figge MT+ (2014) Virulent strain of Lichtheimia corymbifera shows increased phagocytosis by macrophages as revealed by automated microscopy image analysis. Mycoses 57, Suppl. 3, 56-66, */+authors contributed equally.

Lopez CM, Wallich R, Riesbeck K, Skerka C, Zipfel PF (2014) Candida albicans uses the surface protein Gpm1 to attach to human endothelial cells and to keratinocytes via the adhesive protein vitronectin. PLOS One 9, e90796.

Macabeo AP, Martinez FP, Kurtan T, Toth L, Mandi A, Schmidt S, Heilmann J, Alejandro GJ, Knorn M, Dahse HM, Franzblau SG (2014) Tetrahydroxanthene-1,3(2H)-dione derivatives from Uvaria valderramensis. J Nat Prod 77, 2711-2715.

Mehta G, Ferreira VP, Skerka C, Zipfel PF, Banda NK (2014) New insights into disease- specific absence of complement factor H related protein C in mouse models of spon-taneous autoimmune diseases. Mol Immunol 62, 235-248.

Mohan S, Hertweck C, Dudda A, Hammer-schmidt S, Skerka C, Hallström T, Zipfel PF (2014) Tuf of Streptococcus pneumoniae is a surface displayed human complement regulator binding protein. Mol Immunol 62, 249-264.

Noone D, Waters A, Pluthero FG, Geary DF, Kirschfink M, Zipfel PF, Licht C (2014) Successful treatment of DEAP-HUS with eculizumab. Pediatr Nephrol 29, 841-851.

Pauly D, Nagel BM, Reinders J, Killian T, Wulf M, Ackermann S, Ehrenstein B, Zipfel PF, Skerka C, Weber BH (2014) A novel antibody against human properdin inhibits the alter-native complement system and specifically detects properdin from blood samples. PLOS One 9, e96371.

Poolpol K, Orth-Höller D, Speth C, Zipfel PF, Skerka C, de Córdoba SR, Brockmeyer J, Bielaszewska M, Würzner R (2014) Inter-action of Shiga toxin 2 with complement regulators of the factor H protein family. Mol Immunol 58, 77-84.

Schieferdecker S, König S, Weigel C, Dahse HM, Werz O, Nett M (2014) Structure and biosynthetic assembly of gulmirecins, macrolide antibiotics from the predatory

bacterium Pyxidicoccus fallax. Chem Eur J 20, 15933-15940.

Schwenk D, Nett M, Dahse HM, Horn U, Blanchette RA, Hoffmeister D (2014) Inju-ry-induced biosynthesis of methyl-branched polyene pigments in a white-rotting basidio-mycete. J Nat Prod 77, 2658-2663.

Singh B, Su YC, Al-Jubair T, Mukherjee O, Hallström T, Mörgelin M, Blom AM, Riesbeck K (2014) A fine-tuned interaction between trimeric autotransporter haemophilus surface fibrils and vitronectin leads to serum resistance and adherence to respiratory epithelial cells. Infect Immun 82, 2378-2389.

Watson R, Lindner S, Bordereau P, Hunze EM, Tak F, Ngo S, Zipfel PF, Skerka C, Dragon-Durey MA, Marchbank KJ (2014) Standardisation of the factor H autoantibody assay. Immunobiology 219, 9-16.

Weinberger AW, Eddahabi C, Carstesen D, Zipfel PF, Walter P, Skerka C (2014) Human complement factor H and factor H-like protein 1 are expressed in human retinal pigment epithelial cells. Ophthalmic Res 51, 59-66.

Bradley DT, Bourke TW, Fairley DJ, Borrow R, Shields MD, Zipfel PF, Hughes AE (2015) Susceptibility to invasive meningococcal dis-ease: polymorphism of complement system genes and Neisseria meningitidis factor H binding protein. PLOS One 10, e0120757.

Duehring S, Germerodt S, Skerka C, Zipfel PF, Dandekar T, Schuster S (2015) Host-pathogen interactions between the human innate immune system and Candida albicans – Understanding and modeling de-fense and evasion strategies. Front Microbiol 6, 625.

Garrone A, Archipowa N, Zipfel PF, Hermann G, Dietzek B (2015) Plant protochlorophyllide oxidoreductases A and B - Catalytic efficien-cy and initial reaction steps. J Biol Chem 290, 28530-28539.

Genewsky A, Jost I, Busch C, Huber C, Stindl J, Skerka C, Zipfel PF, Rohrer B, Strauß O (2015) Activation of endogenously ex-pressed ion channels by active complement in the retinal pigment epithelium. Pflugers Arch 467, 2179-2191.

Hallström T, Uhde M, Singh B, Skerka C, Riesbeck K, Zipfel PF (2015) Pseudomonas aeruginosa uses dihydrolipoamide dehydro-


genase (Lpd) to bind to the human terminal pathway regulators vitronectin and clusterin to inhibit terminal pathway complement attack. PLOS One 10, e0137630.

Kalb D, Heinekamp T, Lackner G, Scharf DH, Dahse HM, Brakhage AA, Hoffmeister D (2015) Genetic engineering activates biosyn-thesis of aromatic fumaric acid amides in the human pathogen Aspergillus fumigatus. Appl Environ Microbiol 81, 1594-1600.

Kloppot P, Selle M, Kohler C, Stentzel S, Fuchs S, Liebscher V, Müller E, Kale D, Ohlsen K, Bröker BM, Zipfel PF, Kahl BC, Ehricht R, Hecker M, Engelmann S (2015) Microarray based identification of human antibodies against Staphylococcus aureus antigens. Proteomics Clin Appl 9, 1003-1011.

Koenigs A, Zipfel PF, Kraiczy P (2015) Trans-lation elongation factor tuf of Acinetobacter baumannii is a plasminogen-binding protein. PLOS One 10, e0138398.

Kohler S, Hallström T, Singh B, Riesbeck K, Sparta G, Zipfel PF, Hammerschmidt S (2015) Binding of vitronectin and factor H to Hic contributes to immune evasion of Strep-tococcus pneumoniae serotype 3. Thromb Haemost 113, 125-142.

Korp J, König S, Schieferdecker S, Dahse HM, König GM, Werz O, Nett M (2015) Harnessing enzymatic promiscuity in myxochelin biosynthesis for the production of 5-lipoxygenase inhibitors. ChemBioChem 16, 2445-2450.

Luo S, Hipler UC, Münzberg C, Skerka C, Zipfel PF (2015) Sequence variations and protein expression levels of the two immune evasion proteins Gpm1 and Pra1 influence virulence of clinical Candida albicans isolates. PLOS One 10, e0113192.

Mattern DJ, Schoeler H, Weber J, Novoh- radská S, Kraibooj K, Dahse HM, Hillmann F, Valiante V, Figge MT, Brakhage AA (2015) Identification of the antiphagocytic trypaci-din gene cluster in the human-pathogenic fungus Aspergillus fumigatus. Appl Microbiol Biotechnol 99, 10151-10161.

Nester CM, Barbour T, de Cordoba SR, Drag-on-Durey MA, Fremeaux-Bacchi V, Goodship TH, Kavanagh D, Noris M, Pickering M, San-chez-Corral P, Skerka C, Zipfel PF, Smith RJ (2015) Atypical a HUS: State of the art. Mol Immunol 67, 31-42.

Schieferdecker S, König S, Koeberle A, Dahse HM, Werz O, Nett M (2015) Myxoche-lins target human 5-lipoxygenase. J Nat Prod 78, 335-338.

Shabuer G, Ishida K, Pidot SJ, Roth M, Dahse HM, Hertweck C (2015) pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory. Science 350, 670-674.

Singh B, Al-Jubair T, Voraganti C, Andersson T, Mukherjee O, Su YC, Zipfel PF, Riesbeck K (2015) Moraxella catarrhalis binds plasmin-ogen to evade host innate immunity. Infect Immun 83, 3458-3469.

Sugimoto Y, Ishida K, Traitcheva N, Busch B, Dahse HM, Hertweck C (2015) Freedom and constraint in engineered noncolinear polyketide assembly lines. Chem Biol 22, 229-240.

Tyagi C, Bathke J, Goyal S, Fischer M, Dahse HM, Chacko S, Becker K, Grover A (2015) Targeting the intersubunit cavity of Plasmo-dium falciparum glutathione reductase by a novel natural inhibitor: Computational and experimental evidence. Int J Biochem Cell Biol 61, 72-80.

Zipfel PF, Skerka C, Chen Q, Wiech T, Goodship T, Johnson S, Fremeaux-Bacchi V, Nester C, Córdoba SR, Noris M, Pickering M, Smith R (2015) The role of complement in C3 glomerulopathy. Mol Immunol 67, 21-30.

Department Microbial Pathogenicity Mechanisms

Brunke S, Hube B (2014) Adaptive prediction as a strategy in microbial infections. PLOS Pathog 10, e1004356.

Brunke S, Seider K, Fischer D, Jacobsen ID, Kasper L, Jablonowski N, Wartenberg A, Bader O, Enache-Angoulvant A, Schaller M, d’Enfert C, Hube B (2014) One small step for a yeast - Microevolution within macro-phages renders Candida glabrata hypervir-ulent due to a single point mutation. PLOS Pathog 10, e1004478.

Brunke S, Seider K, Richter ME, Bremer-Streck S, Ramachandra S, Kiehntopf M, Brock M, Hube B (2014) Histidine degra-dation via an aminotransferase increases the nutritional flexibility of Candida glabrata. Eukaryot Cell 13, 758-765.

Ene IV, Brunke S, Brown AJ, Hube B (2014) Metabolism in fungal pathogenesis. Cold Spring Harb Perspect Med 4, 12.

Jacobsen ID, Lüttich A, Kurzai O, Hube B, Brock M (2014) In vivo imaging of dissem-inated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy. J Antimicrob Chemother 69, 2785-2796.

Kasper L, Seider K, Gerwien F, Allert S, Brunke S, Schwarzmüller T, Ames L, Zubiria-Barrera C, Mansour MK, Becken U, Barz D, Vyas JM, Reiling N, Haas A, Haynes K, Kuchler K, Hube B (2014) Identification of Candida glabrata genes involved in pH mod-ulation and modification of the phagosomal environment in macrophages. PLOS One 9, e96015.


Miramón P, Dunker C, Kasper L, Jacobsen ID, Barz D, Kurzai O, Hube B (2014) A family of glutathione peroxidases contributes to ox-idative stress resistance in Candida albicans. Med Mycol 52, 223-239.

Quintin J, Voigt J, van der Voort R, Jacobsen ID, Verschueren I, Hube B, Giamarellos-Bour-boulis EJ, van der Meer JW, Joosten LA, Kurzai O, Netea MG (2014) Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompro-mised mice. Eur J Immunol 44, 2405-2414.

Ramachandra S, Linde J, Brock M, Guthke R, Hube B, Brunke S (2014) Regulatory networks controlling nitrogen sensing and uptake in Candida albicans. PLOS One 9, e92734.

Schwarzmüller T, Ma B, Hiller E, Istel F, Tscherner M, Brunke S, Ames L, Firon A, Green B, Cabral V, Marcet-Houben M, Jacob-sen ID, Quintin J, Seider K, Frohner I, Glaser W, Jungwirth H, Bachellier-Bassi S, Chauvel M, Zeidler U, Ferrandon D, Gabaldón T, Hube B, d‘Enfert C, Rupp S, Cormack B, Haynes K, Kuchler K (2014) Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes. PLOS Pathog 10, e1004211.

134

Seider K, Gerwien F, Kasper L, Allert S, Brunke S, Jablonowski N, Schwarzmüller T, Barz D, Rupp S, Kuchler K, Hube B (2014) Immune evasion, stress resistance, and efficient nutrient acquisition are crucial for intracellular survival of Candida glabrata with-in macrophages. Eukaryot Cell 13, 170-183.

Tyc KM, Kühn C, Wilson D, Klipp E (2014) Assessing the advantage of morphological changes in Candida albicans: a game theoret-ical study. Front Microbiol 5, 41.

Voigt J, Hünniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, Löffler J, Kurzai O (2014) Human natural killer cells acting as phago-cytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis 209, 616-626.

Wartenberg A, Linde J, Martin R, Schrei-ner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d‘Enfert C, Brunke S, Hube B (2014) Microevolution of Candida albicans in mac-rophages restores filamentation in a nonfila-mentous mutant. PLOS Genet 10, e1004824.

Wilson D, Mayer FL, Miramón P, Citiulo F, Slesiona S, Jacobsen ID, Hube B (2014) Dis-tinct roles of Candida albicans-specific genes in host-pathogen interactions. Eukaryot Cell 13, 977-989.

Böttcher B, Palige K, Jacobsen ID, Hube B, Brunke S (2015) Csr1/Zap1 maintains zinc homeostasis and influences virulence in Candida dubliniensis but is not coupled to morphogenesis. Eukaryot Cell 14, 661-670.

Brunke S, Quintin J, Kasper L, Jacobsen ID, Richter ME, Hiller E, Schwarzmüller T, d‘Enfert C, Kuchler K, Rupp S, Hube B, Ferrandon D (2015) Of mice, flies – and men? Comparing fungal infection models for large-scale screening efforts. Dis Model Mech 8, 473-486.

Gabrielli E, Pericolini E, Luciano E, Sabbatini S, Roselletti E, Perito S, Kasper L, Hube B, Vecchiarelli A (2015) Induction of caspase-11 by aspartyl proteinases of Candida albicans and implication in promoting inflammatory response. Infect Immun 83, 1940-1948.

Hube B, Hay R, Brasch J, Veraldi S, Schaller M (2015) Dermatomycoses and inflamma-tion: The adaptive balance between growth,

damage, and survival. J Mycol Med 25, e44-e58.

Jahns F, Wilhelm A, Jablonowski N, Mothes H, Greulich KO, Glei M (2015) Butyrate modulates antioxidant enzyme expression in malignant and non-malignant human colon tissues. Mol Carcinog. 54,249-60.

Kasper L, Miramón P, Jablonowski N, Wisgott S, Wilson D, Brunke S, Hube B (2015) Antifungal activity of clotrimazole against Candida albicans depends on carbon sources, growth phase, and morphology. J Med Microbiol 64, 714-723.

Kasper L, Seider K, Hube B (2015) Intracel-lular survival of Candida glabrata in macro-phages: immune evasion and persistence. FEMS Yeast Res 15, fov042.

Pérez-Torrado R, Llopis S, Perrone B, Gómez-Pastor R, Hube B, Querol A (2015) Comparative genomic analysis reveals a critical role of de novo nucleotide biosynthe-sis for Saccharomyces cerevisiae virulence. PLOS One 10, e0122382.

Pericolini E, Gabrielli E, Amacker M, Kasper L, Roselletti E, Luciano E, Sabbatini S, Kaeser M, Moser C, Hube B, Vecchiarelli A, Cassone A (2015) Secretory aspartyl proteinases cause vaginitis and can mediate vaginitis caused by Candida albicans in mice. mBio 6, e00724.

Department Molecular and Applied Microbiology


Bacher P, Kniemeyer O, Schönbrunn A, Sawitzki B, Assenmacher M, Rietschel E, Steinbach A, Cornely OA, Brakhage AA, Thiel A, Scheffold A (2014) Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against muco-sal fungi. Mucosal Immunol 7, 916-928.

Bacher P, Kniemeyer O, Teutschbein T, Thoen M, Vödisch M, Wartenberg D, Scharf DH, Koester-Eiserfunke N, Schütte M, Dübel S, Assenmacher M, Brakhage AA, Scheffold A (2014) Identification of immunogenic antigens from Aspergillus fumigatus by direct multi-parameter characterization of specific

conventional and regulatory CD4+ T cells. J Immunol 197, 3332-3343.

Bayry J, Beaussart A, Dufrêne YF, Sharma M, Bansal K, Kniemeyer O, Aimanianda V, Brakhage AA, Kaveri SV, Kwon-Chung KJ, Latgé JP, Beauvais A (2014) Surface struc-ture characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response. Infect Immun 82, 3141-3153.

Benoit I, van den Esker MH, Patyshakuliyeva A, Mattern DJ, Blei F, Zhou M, Dijksterhuis J, Brakhage AA, Kuipers OP, de Vries RP, Kovács AT (2014) Bacillus subtilis attach-ment to Aspergillus niger hyphae results in mutually altered metabolism. Environ Microbiol 17, 2099-2113.


de A. Santiago ALCM, Hoffmann K, Lima DX, de Oliveira RJV, Vieira HEE, Malosso E, Maia LC, da Silva GA (2014) A new species of Lichtheimia (Mucoromycotina, Mucorales) isolated from Brazilian soil. Mycol Progress 13, 343-352.

de Hoog S, Ibrahim AS, Voigt K (2014) Zygo-mycetes: an emerging problem in the clinical laboratory. Mycoses 57, Suppl. 3, 1.

El-Shabrawi MH, Kamal NM, Kaerger K, Voigt K (2014) Diagnosis of gastrointestinal basidiobolomycosis: a mini-review. Mycoses 57, Suppl. 3, 138-143.

Grützmann K, Szafranski K, Pohl M, Voigt K, Petzold A, Schuster S (2014) Fungal alterna-tive splicing is associated with multicellular complexity and virulence: a genome-wide multi-species study. DNA Res 21, 27-39.

Gsaller F, Hortschansky P, Beattie SR, Klam-mer V, Tuppatsch K, Lechner BE, Rietzschel N, Werner ER, Vogan AA, Chung D, Mühlen-hoff U, Kato M, Cramer RA, Brakhage AA, Haas H (2014) The janus transcription factor HapX controls fungal adaptation to both iron starvation and iron excess. EMBO J 33, 2261-2276.

Habel A, Scharf DH, Heinekamp T, Brak- hage AA, Hertweck C (2014) Opposed


effects of enzymatic gliotoxin N-and S-meth-ylations. J Am Chem Soc 136, 11674-11679.

Hillmann F, Linde J, Beckmann N, Cyrulies M, Strassburger M, Heinekamp T, Haas H, Guthke R, Kniemeyer O, Brakhage AA (2014) The novel globin protein fungoglobin is involved in low oxygen adaptation of Asper-gillus fumigatus. Mol Microbiol 93, 539-553.

Horn F, Schroeckh V, Netzker T, Guthke R, Brakhage AA, Linde J (2014) Draft genome sequence of Streptomyces iranensis. Genome Announc 2, e00616-14.


Kroll K, Pähtz V, Hillmann F, Vaknin Y, Schmidt-Heck W, Roth M, Jacobsen ID, Os-herov N, Brakhage AA, Kniemeyer O (2014) Identification of hypoxia-inducible target genes of Aspergillus fumigatus by transcrip-tome analysis reveals cellular respiration as important contributor to hypoxic survival. Eukaryot Cell 13, 1241-1253.

Kroll K, Pähtz V, Kniemeyer O (2014) Elucidating the fungal stress response by proteomics. J Proteomics 97, 151-163.

Lapp K, Vödisch M, Kroll K, Strassburger M, Kniemeyer O, Heinekamp T, Brakhage AA (2014) Characterisation of the Aspergillus fumigatus detoxification systems for reactive nitrogen intermediates and impact on viru-lence. Frontiers in Microbiology 5, 469.

Linde J, Schwartze V, Binder U, Lass-Flörl C, Voigt K, Horn F (2014) De novo whole-ge-nome sequence and genome annotation of Lichtheimia ramosa. Genome Announc 2, e00888-14.

Park HR, Voigt K (2014) Interaction of Zgomycetes with innate immune cells recon-sidered with respect to ecology, morphology, evolution and infection biology: a mini-re-view. Mycoses 57, Suppl. 3, 31-39.

Perez-Nadales E, Almeida Nogueira MF, Baldin C, Castanheira S, El Ghalid M, Grund E, Lengeler K, Marchegiani E, Mehrotra PV, Moretti M, Naik V, Oses-Ruiz M, Oskarsson T, Schäfer K, Wasserstrom L, Brakhage AA, Gow NA, Kahmann R, Lebrun MH, Pe-

rez-Martin J, Di Pietro A, Talbot NJ, Toquin V, Walther A, Wendland J (2014) Fungal model systems and the elucidation of pathoge-nicity determinants. Fungal Genet Biol 70C, 42-67.

Scharf DH, Groll M, Habel A, Heinekamp T, Hertweck C, Brakhage AA, Huber EM (2014) Flavoenzyme-catalyzed formation of disul-fide bonds in natural products. Angew Chem Int Ed 53, 2221-2224.

Scharf DH, Habel A, Heinekamp T, Brak-hage AA, Hertweck C (2014) Opposed ef-fects of enzymatic gliotoxin N- and S-methyl-ations. J Am Chem Soc 136, 11674-11679.

Schieferdecker S, König S, Weigel C, Dahse HM, Werz O, Nett M (2014) Structure and biosynthetic assembly of gulmirecins, macrolide antibiotics from the predatory bacterium Pyxidicoccus fallax. Chem Eur J 20, 15933-15940.

Schoch CL, Robbertse B, Robert V, Vu D, Cardinali G, Irinyi L, Meyer W, Nilsson RH, Hughes K, Miller AN, Kirk PM, Abarenkov K, Aime MC, Ariyawansa HA, Bidartondo M, Boekhout T, Buyck B, Cai Q, Chen J, Crespo A, Crous PW, Damm U, De Beer ZW, Dentinger BT, Divakar PK, Dueñas M, Feau N, Fliegerova K, García MA, Ge ZW, Griffith GW, Groenewald JZ, Groenewald M, Grube M, Gryzenhout M, Gueidan C, Guo L, Hambleton S, Hamelin R, Hansen K, Hofstetter V, Hong SB, Houbraken J, Hyde KD, Inderbitzin P, Johnston PR, Karunarath-na SC, Kõljalg U, Kovács GM, Kraichak E, Krizsan K, Kurtzman CP, Larsson KH, Leavitt S, Letcher PM, Liimatainen K, Liu JK, Lodge DJ, Luangsa-ard JJ, Lumbsch HT, Maharac-hchikumbura SS, Manamgoda D, Martín MP, Minnis AM, Moncalvo JM, Mulè G, Nakasone KK, Niskanen T, Olariaga I, Papp T, Petkovits T, Pino-Bodas R, Powell MJ, Raja HA, Re-decker D, Sarmiento-Ramirez JM, Seifert KA, Shrestha B, Stenroos S, Stielow B, Suh SO, Tanaka K, Tedersoo L, Telleria MT, Udayanga D, Untereiner WA, Diéguez Uribeondo J, Subbarao KV, Vágvölgyi C, Visagie C, Voigt K, Walker DM, Weir BS, Weiß M, Wijayawardene NN, Wingfield MJ, Xu JP, Yang ZL, Zhang N, Zhuang WY, Federhen S (2014) Finding nee-dles in haystacks: linking scientific names, reference specimens and molecular data for Fungi. Database (Oxford), doi 10.1093, 1-21

Schwartze VU, de A. Santiago ALCM, Jacobsen ID, Voigt K (2014) The pathogenic potential of the Lichtheimia genus revisited:

Lichtheimia brasiliensis is a novel, non-patho-genic species. Mycoses 57, Suppl. 3, 128-131.

Schwartze VU, Jacobsen ID (2014) Mucor-mycoses caused by Lichtheimia species. Mycoses 57, Suppl. 3, 73-78.

Schwartze VU, Winter S, Shelest E, Marcet-Houben M, Horn F, Wehner S, Linde J, Valiante V, Sammeth M, Riege K, Nowrousian M, Kaerger K, Jacobsen ID, Marz M, Brakhage AA, Gabaldón T, Böcker S, Voigt K (2014) Gene expansion shapes genome architecture in the human pathogen Lichtheimia corymbifera: an evolutionary genomics analysis in the ancient terrestrial Mucorales (Mucoromycotina). PLOS Genetics 10, e1004496.

Stubendorff B, Finke S, Walter M, Kniemeyer O, von Eggeling F, Gruschwitz T, Steiner T, Ott U, Wolf G, Wunderlich H, Junker K (2014) Urine protein profiling identified alpha-1-mi-croglobulin and haptoglobin as biomarkers for early diagnosis of acute allograft rejec-tion following kidney transplantation. World J Urol 32, 1619-1624.

Unkles SE, Valiante V, Mattern DJ, Brak-hage AA (2014) Synthetic biology tools for bioprospecting of natural products in eukaryotes. Chem Biol 21, 502-508.

Altwasser R, Baldin C, Weber J, Guthke R, Kniemeyer O, Brakhage AA, Linde J, Valian-te V (2015) Network modeling reveals cross talk of MAP kinases during adaptation to caspofungin stress in Aspergillus fumigatus. PLOS One 10, e0136932.

Bacher P, Jochheim-Richter A, Mockel-Ten-brink N, Kniemeyer O, Wingenfeld E, Alex R, Ortigao A, Karpova D, Lehrnbecher T, Ullmann AJ, Hamprecht A, Cornely O, Brakhage AA, Assenmacher M, Bonig H, Scheffold A (2015) Clinical-scale isolation of the total Aspergillus fumigatus-reactive T-helper cell repertoire for adoptive transfer. Cytotherapy 17, 1396-1405.

Bacher P, Steinbach A, Kniemeyer O, Ham-precht A, Assenmacher M, Vehreschild MJ, Vehreschild JJ, Brakhage AA, Cornely OA, Scheffold A (2015) Fungus-specific CD4(+) T cells for rapid identification of invasive pulmonary mold infection. Am J Respir Crit Care Med 191, 348-352.

Baldin C, Valiante V, Krüger T, Schafferer L, Haas H, Kniemeyer O, Brakhage AA (2015)

136

Comparative proteomics of a tor inducible Aspergillus fumigatus mutant reveals involve-ment of the Tor kinase in iron regulation. Proteomics 15, 2230-2243.

Gallmetzer A, Silvestrini L, Schinko T, Gesslbauer B, Hortschansky P, Dattenböck C, Muro-Pastor MI, Kungl A, Brakhage AA, Scazzocchio C, Strauss J (2015) Reversible oxidation of a conserved methionine in the nuclear export sequence determines subcellular distribution and activity of the fungal nitrate regulator NirA. PLOS Genet 11, e1005297.

Gressler M, Hortschansky P, Geib E, Brock M (2015) A new high-performance heterol-ogous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front Microbiol 6, 184.


Hillmann F, Novohradská S, Mattern DJ, Forberger T, Heinekamp T, Westermann M, Winckler T, Brakhage AA (2015) Virulence determinants of the human pathogenic fungus Aspergillus fumigatus protect against soil amoeba predation. Environ Microbiol 17, 2858-2869.

Hillmann F, Shekhova E, Kniemeyer O (2015) Insights into the cellular responses to hypoxia in filamentous fungi. Curr Genet 61, 441-455.


Horn F, Linde J, Mattern DJ, Walther G, Guthke R, Brakhage AA, Valiante V (2015) Draft genome sequence of the fungus Peni- cillium brasilianum MG11. Genome Announc 3, e00724-15.

Hortschansky P, Ando E, Tuppatsch K, Arikawa H, Kobayashi T, Kato M, Haas H, Brakhage AA (2015) Deciphering the combinatorial DNA-binding code of the CCAAT-binding complex and the iron-reg-

ulatory basic region leucine zipper (bZIP) transcription factor HapX. J Biol Chem 290, 6058-6070.

Kaerger K, Schwartze VU, Dolatabadi S, Nyilasi I, Kovács SA, Binder U, Papp T, Hoog Sd, Jacobsen ID, Voigt K (2015) Adaptation to thermotolerance in Rhizopus coincides with virulence as revealed by avian and invertebrate infection models, phylogeny, physiological and metabolic flexibility. Viru-lence 6, 395-403.


Kraibooj K*, Schoeler H*, Svensson CM, Brakhage AA, Figge MT (2015) Automated quantification of the phagocytosis of As-pergillus fumigatus conidia by a novel image analysis algorithm. Frontiers in Microbiology 6, 549. *authors contributed equally

Lin CJ, Sasse C, Gerke J, Valerius O, Irmer H, Frauendorf H, Heinekamp T, Straßburger M, Tran VT, Herzog B, Braus-Stromeyer SA, Braus GH (2015) Transcription factor somA is required for adhesion, development and virulence of the human pathogen Aspergillus fumigatus. PLOS Pathogens 11,e1005205.

Macheleidt J, Scherlach K, Neuwirth T, Schmidt-Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Hert-weck C, Heinekamp T, Brakhage AA (2015) Transcriptome analysis of cAMP-dependent protein kinase A regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus. Mol Microbiol 96, 148-162.

Mattern DJ, Schoeler H, Weber J, No-vohradská S, Kraibooj K, Dahse HM, Hill-mann F, Valiante V, Figge MT, Brakhage AA (2015) Identification of the antiphagocytic trypacidin gene cluster in the human-patho-genic fungus Aspergillus fumigatus. Applied Microbiology and Biotechnology 99, 10151-10161.

Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Mo-rales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escriba-

no JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O‘Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11, 625-631.

Münchberg U, Wagner L, Rohrer C, Voigt K, Rösch P, Jahreis G, Popp J (2015) Quan-titative assessment of the degree of lipid unsaturation in intact mortierella by Raman microspectroscopy. Anal Bioanal Chem 407, 3303-3311.

Rambach G, Blum G, Latgé JP, Fontaine T, Heinekamp T, Hagleitner M, Jeckström H, Weigel G, Würtinger P, Pfaller K, Krappmann S, Löffler J, Lass-Flörl C, Speth C (2015) Identification of Aspergillus fumigatus sur-face components that mediate interaction of conidia and hyphae with human platelets. J Infect Dis 212,1140-9.

Rauscher S, Pacher S, Hedtke M, Kniemeyer O, Fischer R (2015) A phosphorylation code of the Aspergillus nidulans global regulator VelvetA (VeA) determines specific functions. Mol Microbiol 99, 909-24.


Valiante V, Monteiro MC, Martín J, Altwasser R, El Aouad N, González I, Kniemeyer O, Mel-lado E, Palomo S, de Pedro N, Pérez-Victoria I, Tormo JR, Vicente F, Reyes F, Genilloud O, Brakhage AA (2015) Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010). Antimicrob Agents Chemother 59, 5145-5153.

Wagner K, Krause K, David A, Kai M, Jung EM, Sammer D, Kniemeyer O, Boland W, Kothe E (2015) Influence of zygomycete-de-rived D‘orenone on IAA signaling in Tricholo-ma-spruce ectomycorrhiza. Environ Microbiol 18, 2470-80.

Wagner K, Linde J, Krause K, Gube M, Koestler T, Sammer D, Kniemeyer O, Kothe E (2015) Tricholoma vaccinum host commu-nication during ectomycorrhiza formation. FEMS Microbiol Ecol 91, 11.

Wlaź P, Knaga S, Kasperek K, Wlaź A, Poleszak E, Jeżewska-Witkowska G, Win-iarczyk S, Wyska E, Heinekamp T, Rundfeldt C (2015) Activity and safety of inhaled itraconazole nanosuspension in a model pulmonary Aspergillus fumigatus infection in inoculated young Quails. Mycopathologia 180, 35-42.

Department Cell and Molecular Biology


Böcker S, Heurich A, Franke C, Monajem-bashi S, Sachse K, Saluz HP, Hänel F (2014) Chlamydia psittaci inclusion membrane protein IncB associates with host protein Snapin. Int J Med Microbiol 304, 542-553.

Fatangare A, Gebhardt P, Saluz H, Svatoš A (2014) Comparing 2-[(18)F]fluoro-2-de-oxy-D-glucose and [(68)Ga]gallium-citrate translocation in Arabidopsis thaliana.Nucl Med Biol 41, 737-743.

Groot AT, Schöfl G, Inglis O, Donnerhacke S, Classen A, Schmalz A, Santangelo RG, Emerson J, Gould F, Schal C, Heckel DG (2014) Within-population variability in a moth sex pheromone blend: genetic basis and behavioural consequences. Proc Biol Sci 281, 20133054.

Irmler IM, Gebhardt P, Hoffmann B, Opfer- mann T, Figge MT, Saluz HP, Kamradt T (2014) 18 F-Fluoride positron emission tomography/computed tomography for non-invasive in vivo quantification of pathophys-iological bone metabolism in experimental murine arthritis. Arthritis Res Ther 16, R155.

Schnerwitzki D, Perner B, Hoppe B, Pietsch S, Mehringer R, Hänel F, Englert C (2014) Al-ternative splicing of Wilms tumor suppressor 1 (Wt1) exon 4 results in protein isoforms with different functions. Dev Biol 393, 24-32.

Kästner J, Saluz HP, Hänel F (2015) Identi-fication of in vivo-induced bacterial protein antigens during calf infection with Chlamydia psittaci. Int J Med Microbiol 305, 310-321.

Krügel H, Klimina KM, Mrotzek G, Tretyakov A, Schöfl G, Saluz HP, Brantl S, Poluektova EU, Danilenko VN (2015) Expression of the toxin-antitoxin genes yefM, yoeB in human Lactobacillus rhamnosus isolates. J Basic Microbiol 55, 982-991.

Muslihudeen AA, Schöfl G, Mrotzek G, Haryanti H, Sugama K, Saluz HP (2015) Population structure of the Indonesian giant tiger shrimp Penaeus monodon: a window into evolutionary similarities between paralogous mitochondrial DNA sequences and their genomes. Ecology and Evolution 5, 3570-3584.

Walther E, Richter M, Xu Z, Kramer C, von Grafenstein S, Kirchmair J, Grienke U, Rollinger JM, Liedl KR, Slevogt H, Sauerbrei A, Saluz HP, Pfister W, Schmidtke M (2015) Antipneumococcal activity of neuramidase inhibiting artocarpin. Int J Med Microbiol 305, 289-297.

Research Group Applied Systems Biology

Hünniger K*, Lehnert T*, Bieber K, Martin R, Figge MT+, Kurzai O+ (2014) A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood. PLOS Comput Biol 10, e1003479, */+authors contributed equally.

Irmler IM, Gebhardt P, Hoffmann B, Opfer- mann T, Figge MT, Saluz HP, Kamradt T (2014) 18 F-Fluoride positron emission tomography/computed tomography for non-invasive in vivo quantification of pathophys-iological bone metabolism in experimental murine arthritis. Arthritis Res Ther 16, R155.



Pollmächer J, Figge MT (2014) Agent-based model of human alveoli predicts chemotac-tic signaling by epithelial cells during early Aspergillus fumigatus infection. PLOS ONE 9, e111630.

Svensson CM, Krusekopf S, Lücke J, Figge MT (2014) Automated detection of circulating tumor cells with naive Bayesian classifiers. Cytometry A 85, 501-511.

Brandes S, Mokhtari Z, Essig F, Hünniger K, Kurzai O, Figge MT (2015) Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neutrophils. Medical Image Analysis 20, 34-51.

Duggan S, Essig F, Hünniger K, Mokhtari Z, Bauer L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O (2015) Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17, 1259-1276.

Essig F, Hünniger K, Dietrich S, Figge MT, Kurzai O (2015) Human neutrophils dump Candida glabrata after intracellular killing. Fungal Genetics and Biology 84, 37-40.

Figge MT (2015) Image-based Systems Biol-ogy: what you get is more than you can see. G.I.T. Laboratory Journal Europe 19, 13-15.

Figge MT, Murphy RF (2015) Image-based Systems Biology. Cytometry A 87, 459-461.

Hünniger K, Bieber K, Martin R, Lehnert T, Figge MT, Löffler J, Guo R, Riedemann N, Kurzai O (2015) A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphyla-toxin C5a. J Immunol 194, 1199-1210.

138

Kraibooj K*, Schoeler H*, Svensson CM, Brakhage AA, Figge MT (2015) Automated quantification of the phagocytosis of As-pergillus fumigatus conidia by a novel image analysis algorithm. Frontiers in Microbiology 6, 549. *authors contributed equally

Lehnert T*, Timme S*, Pollmächer J, Hünni-ger K, Kurzai O, Figge MT (2015) Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions. Frontiers Microbiol 6, 608. *au-thors contributed equally

Mahler L, Tovar M, Weber T, Brandes S, Rudolph MM, Ehgartner J, Mayr T, Figge MT, Roth M, Zang E (2015) Enhanced and homogeneous oxygen availability during incubation of microfluidic droplets. RSC Advances 5, 101871-101878.

Mattern DJ, Schoeler H, Weber J, No-vohradská S, Kraibooj K, Dahse HM, Hill-mann F, Valiante V, Figge MT, Brakhage AA (2015) Identification of the antiphagocytic trypacidin gene cluster in the human-patho-genic fungus Aspergillus fumigatus. Applied Microbiology and Biotechnology 99, 10151-10161.

Medyukhina A, Timme S, Mokhtari Z, Figge MT (2015) Image-based systems biology of infection. Cytometry A 87, 462-470.

Mokhtari Z*, Mech F*, Zehentmeier S, Hau-ser AE, Figge MT (2015) Quantitative image analysis of cell colocalization in murine bone marrow. Cytometry A 87, 503-512. *authors contributed equally

Pollmächer J, Figge MT (2015) Deciphering chemokine properties by a hybrid agent-based model of Aspergillus fumigatus infec-tion in human alveoli. Frontiers Microbiol 6, 503.

Prauße TEM, Schäuble S, Guthke R, Schus-ter S (2015) Computing the various path-ways of penicillin synthesis and their molar yields. Biotech Bioeng 113, 173-181.

Svensson CM, Hübler R, Figge MT (2015) Automated classification of circulating tumor cells and the impact of inter-observer vari-ability on classifier training and performance. J Immunol Res 2015, Article ID 573165, 9.

Research Group Fungal Septomics

Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, Löffler J, Maertens JA,

Bell AS, Inforzato A, Barbati E, Almeida B, Santos e Sousa P, Barbui A, Potenza L, Caira M, Rodrigues F, Salvatori G, Pagano L, Luppi M, Mantovani A, Velardi A, Romani L, Car-valho A (2014) Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med 370, 421-432.

Cunha C, Kurzai O, Carvalho A (2014) PTX3 deficiency and aspergillosis. N Engl J Med 370, 1666-1667.

Cunha C, Kurzai O, Löffler J, Aversa F, Roma-ni L, Carvalho A (2014) Neutrophil responses to aspergillosis: New roles for old players. Mycopathologia 178, 387-93.

Das Gupta M, Fliesser M, Springer J, Breit-schopf T, Schlossnagel H, Schmitt AL, Kur-zai O, Hünniger K, Einsele H, Löffler J (2014) Aspergillus fumigatus induces microRNA-132 in human monocytes and dendritic cells. Int J Med Microbiol 304, 592-596.

Ekaney ML, Otto GP, Sossdorf M, Sponholz C, Boehringer M, Loesche W, Rittirsch D, Wil-harm A, Kurzai O, Bauer M, Claus RA (2014) Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation. Crit Care 18, 543.

Hentschel J, Müller U, Doht F, Fischer N, Böer K, Sonnemann J, Hipler C, Hünniger K, Kurzai O, Markert UR, Mainz JG (2014) Influences of nasal lavage collection-, pro-cessing- and storage methods on inflam-matory markers-evaluation of a method for non-invasive sampling of epithelial lining fluid in cystic fibrosis and other respiratory diseases. J Immunol Methods 404, 41-51.

Hünniger K*, Lehnert T*, Bieber K, Martin R, Figge MT+, Kurzai O+ (2014) A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood. PLOS Comput Biol 10, e1003479, */+authors contributed equally.


Lother J, Breitschopf T, Krappmann S, Morton CO, Bouzani M, Kurzai O, Gunzer M, Hasenberg M, Einsele H, Loeffler J (2014) Human dendritic cell subsets display dis-tinct interactions with the pathogenic mould

Aspergillus fumigatus. Int J Med Microbiol 304, 1160-8.

Martínez-Ramírez JA, Walther G, Peters FT (2014) Studies on drug metabolism by fungi colonizing decomposing human cadavers. Part II: biotransformation of five model drugs by fungi isolated from post-mortem material. Drug Test Analysis 7, 265-79.

Miramón P, Dunker C, Kasper L, Jacobsen ID, Barz D, Kurzai O, Hube B (2014) A family of glutathione peroxidases contributes to oxi-dative stress resistance in Candida albicans. Med Mycol 52, 223-239.



Wartenberg A, Linde J, Martin R, Schrein-er M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d‘Enfert C, Brunke S, Hube B (2014) Microevolution of Candida albicans in mac-rophages restores filamentation in a nonfila-mentous mutant. PLOS Genet 10, e1004824.

Brandes S, Mokhtari Z, Essig F, Hünniger K, Kurzai O, Figge MT (2015) Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neutrophils. Medical Image Analysis 20, 34-51.

Dix A, Hünniger K, Weber M, Guthke R, Kur-zai O, Linde J (2015) Biomarker-based classi-fication of bacterial and fungal whole-blood infections in a genome-wide expression study. Front Microbiol 6, 171.



Essig F, Hünniger K, Dietrich S, Figge MT, Kurzai O (2015) Human neutrophils dump Candida glabrata after intracellular killing. Fungal Genet Biol 84, 37-40.

Fliesser M, Morton CO, Bonin M, Ebel F, Hün-niger K, Kurzai O, Einsele H, Löffler J (2015) Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune respons-es initiated by human dendritic cells. Int J Med Microbiol. 194, 1199-1210.


Hünniger K, Bieber K, Martin R, Lehnert T, Figge MT, Löffler J, Guo R, Riedemann N, Kurzai O (2015) A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphyla-toxin C5a. J Immunol 194, 1199-1210.

Huyke J, Martin R, Walther G, Weber M, Kaerger K, Bougnoux ME, Elias J, Kurzai O (2015) Candida albicans bloodstream isolates in a german university hospital are genetically heterogenous and susceptible to commonly used antifungals. Int J Med Microbiol 305, 742-747.

Huyke J, Martin R, Walther G, Weber M, Kaerger K, Bougnoux ME, Elias J, Kurzai O (2015) Candida albicans bloodstream isolates in a herman university hospital are genetically heterogenous and susceptible to commonly used antifungals. Int J Med Microbiol 305, 742-747.

Lehnert T*, Timme S*, Pollmächer J, Hünni-ger K, Kurzai O, Figge MT (2015) Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions. Frontiers in Microbiology 6, 608.

*authors contributed equally.

Leonhardt I, Spielberg S, Weber M, Albrecht- Eckardt D, Bläss M, Claus R, Barz D, Scher-lach K, Hertweck C, Löffler J, Hünniger K, Kurzai O (2015) The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immu-nity. mBio 6, e00143.

Linde J, Duggan S, Weber M, Horn F, Sieber P, Hellwig D, Riege K, Marz M, Martin R, Guthke R, Kurzai O (2015) Defining the tran-

scriptomic landscape of Candida glabrata by RNA-Seq. Nucleic Acids Res 43, 1392-1406.

Münchberg U, Wagner L, Rohrer C, Voigt K, Rösch P, Jahreis G, Popp J (2015) Quan-titative assessment of the degree of lipid unsaturation in intact Mortierella by Raman microspectroscopy. Anal Bioanal Chem 407, 3303-3311.

Research Group Microbial Immunology

Brunke S, Seider K, Fischer D, Jacobsen ID, Kasper L, Jablonowski N, Wartenberg A, Bader O, Enache-Angoulvant A, Schaller M, d’Enfert C, Hube B (2014) One small step for a yeast – Microevolution within macro-phages renders Candida glabrata hypervir-ulent due to a single point mutation. PLOS Pathog 10, e1004478.

Hebecker B, Naglik JR, Hube B, Jacobsen ID (2014) Pathogenicity mechanisms and host response during oral Candida albicans infec-tions. Expert Rev Anti Infect Ther 12, 867-879.


Krljanac B, Weih D, Jacobsen ID, Hu D, Koliesnik I, Reppe K, Witzenrath M, Weih F (2014) NF-κB2/p100 deficiency impairs im-mune responses to T-cell-independent type 2 antigens. Eur J Immunol 44, 662-672.


Miramón P, Dunker C, Kasper L, Jacobsen ID, Barz D, Kurzai O, Hube B (2014) A family of glutathione peroxidases contributes to ox-idative stress resistance in Candida albicans. Med Mycol 52, 223-239.

Otzen C, Bardl B, Jacobsen ID, Nett M, Brock M (2014) Candida albicans utilizes a modified β-oxidation pathway for the degradation of toxic propionyl-CoA. J Biol Chem 289, 8151-8169.


Schwartze VU, de A. Santiago ALCM, Ja-cobsen ID, Voigt K (2014) The pathogenic potential of the Lichtheimia genus revisited: Lichtheimia brasiliensis is a novel, non-patho-genic species. Mycoses 57, Suppl. 3, 128-131.



Schwarzmüller T, Ma B, Hiller E, Istel F, Tscherner M, Brunke S, Ames L, Firon A, Green B, Cabral V, Marcet-Houben M, Jacob-sen ID, Quintin J, Seider K, Frohner I, Glaser W, Jungwirth H, Bachellier-Bassi S, Chauvel M, Zeidler U, Ferrandon D, Gabaldón T, Hube B, d‘Enfert C, Rupp S, Cormack B, Haynes K, Kuchler K (2014) Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes. PLOS Pathog 10, e1004211.


Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d‘Enfert C, Brunke S, Hube B (2014) Microevolution of Candida albicans in mac-rophages restores filamentation in a nonfila-mentous mutant. PLOS Genet 10, e1004824.

Wilson D, Mayer FL, Miramón P, Citiulo F, Slesiona S, Jacobsen ID, Hube B (2014) Dis-

140

tinct roles of Candida albicans-specific genes in host-pathogen interactions. Eukaryot Cell 13, 977-989.

Böttcher B, Palige K, Jacobsen ID, Hube B, Brunke S (2015) Csr1/Zap1 maintains zinc homeostasis and influences virulence in Candida dubliniensis but is not coupled to morphogenesis. Eukaryot Cell 14, 661-670.

Brunke S, Quintin J, Kasper L, Jacobsen ID, Richter ME, Hiller E, Schwarzmüller T, d‘En-fert C, Kuchler K, Rupp S, Hube B, Ferrandon D (2015) Of mice, flies - and men? Com-paring fungal infection models for large-scale screening efforts. Dis Model Mech 8, 473-486.



Polke M, Hube B, Jacobsen ID (2015) Can-dida survival strategies. Adv Appl Microbiol 91, 139-235.

Research Group Systems Biology and Bioinformatics

Baumgart M, Groth M, Priebe S, Savino A, Testa G, Dix A, Ripa R, Spallotta F, Gaetano C, Ori M, Terzibasi Tozzini E, Guthke R, Platzer M, Cellerino A (2014) RNA-seq of the aging brain in the short-lived fish N. furzeri -con-served pathways and novel genes associat-ed with neurogenesis. Aging Cell 13, 965-974.


Campos G, Schmidt-Heck W, Ghallab A, Rochlitz K, Pütter L, Medinas DB, Hetz C, Widera A, Cadenas C, Begher-Tibbe B, Reif

R, Günther G, Sachinidis A, Hengstler JG, Godoy P (2014) The transcription factor CHOP, a central component of the transcrip-tional regulatory network induced upon CCl4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity. Arch Toxicol 88, 1267-1280.

Grinberg M, Stöber RM, Edlund K, Rempel E, Godoy P, Reif R, Widera A, Madjar K, Schmidt-Heck W, Marchan R, Sachinidis A, Spitkovsky D, Hescheler J, Carmo H, Arbo MD, van de Water B, Wink S, Vinken M, Rogiers V, Escher S, Hardy B, Mitic D, Myatt G, Waldmann T, Mardinoglu A, Damm G, Seehofer D, Nüssler A, Weiss TS, Oberemm A, Lampen A, Schaap MM, Luijten M, van Steeg H, Thasler WE, Kleinjans JC, Stierum RH, Leist M, Rahnenführer J, Hengstler JG (2014) Toxicogenomics directory of chem-ically exposed human hepatocytes. Arch Toxicol 88, 2261-2287.


Horn F, Rittweger M, Taubert J, Lysenko A, Rawlings C, Guthke R (2014) Interactive exploration of integrated biological datasets using context-sensitive workflows. Front Genet 5, 21.

Horn F, Schroeckh V, Netzker T, Guthke R, Brakhage AA, Linde J (2014) Draft genome sequence of Streptomyces iranensis. Genome Announc 2, e00616-14.


Kupfer P, Huber R, Weber M, Vlaic S, Häupl T, Koczan D, Guthke R, Kinne RW (2014) Novel application of multi-stimuli network inference to synovial fibroblasts of rheumatoid arthritis patients. BMC Med Genomics 7, 40-40.

Linde J, Schwartze V, Binder U, Lass-Flörl C, Voigt K, Horn F (2014) De novo whole-ge-nome sequence and genome annotation

of Lichtheimia ramosa. Genome Announc 2, e00888-14.

Manchanda H, Seidel N, Krumbholz A, Sauerbrei A, Schmidtke M, Guthke R (2014) Within-host influenza dynamics: a small-scale mathematical modeling approach. Biosystems 118, 51-59.

Marthandan S, Priebe S, Hemmerich P, Klement K, Diekmann S (2014) Long-term quiescent fibroblast cells transit into senes-cence. PLOS One 9, e115597.

Matz-Soja M, Aleithe S, Marbach E, Böttger J, Arnold K, Schmidt-Heck W, Kratzsch J, Gebhardt R (2014) Hepatic hedgehog signal-ing contributes to the regulation of IGF-I and IGFBP serum levels. Cell Communication and Signaling 12, 11.

Ramachandra S, Linde J, Brock M, Guthke R, Hube B, Brunke S (2014) Regulatory net-works controlling nitrogen sensing and up-take in Candida albicans. PLOS One 9, e92734.

Schleicher J, Guthke R, Dahmen U, Dirsch O, Holzhuetter HG, Schuster S (2014) A theoretical study of lipid accumulation in the liver-implications for nonalcoholic fatty liver disease. Biochim Biophys Acta 1841, 62-69.

Schliess F, Hoehme S, Henkel S, Ghallab A, Driesch D, Böttger J, Guthke R, Pfaff M, Hengstler J, Gebhardt R, Häussinger D, Dras-do D, Zellmer S (2014) Integrated metabolic spatial-temporal model for prediction of ammonia detoxification during liver damage and regeneration. Hepatology 60, 2040-2051


Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d‘Enfert C, Brunke S, Hube B (2014) Microevolution of Candida albicans in mac-rophages restores filamentation in a nonfila-mentous mutant. PLOS Genet 10, e1004824.


Weimer S, Priebs J, Kuhlow D, Groth M, Prie-be S, Mansfeld J, Merry TL, Dubuis S, Laube S, Pfeiffer AF, Schulz TJ, Guthke R, Platzer M, Zamboni N, Zarse K, Ristow M (2014) D-glucosamine supplementation extends lifespan of nematodes and aging mice. Nature Communications 5, 3563.

Woetzel D, Huber R, Kupfer P, Pohlers D, Pfaff M, Driesch D, Häupl T, Koczan D, Stiehl P, Guthke R, Kinne RW (2014) Identification of rheumatoid arthritis and osteoarthritis patients by transcriptome-based rule set generation. Arthritis Res Ther 16, R84.

Zaehle C, Gressler M, Shelest E, Geib E, Hertweck C, Brock M (2014) Terrein biosyn-thesis in Aspergillus terreus and its impact on phytotoxicity. Chem Biol 21, 719-731.

Zhang X, Müller S, Möller M, Huse K, Tau-dien S, Book M, Stuber F, Platzer M, Groth M (2014) 8p23 beta-defensin copy number determination by single-locus pseudogene-based paralog ratio tests risk bias due to low-frequency sequence variations. BMC Genomics 15, 64-64.

Altwasser R, Baldin C, Weber J, Guthke R, Kniemeyer O, Brakhage AA, Linde J, Valiante V (2015) Network modeling reveals cross talk of MAP kinases during adaptation to caspofungin stress in Aspergillus fumigatus. PLOS One 10, e0136932.

Böttger J, Arnold K, Thiel C, Rennert C, Aleithe S, Hofmann U, Vlaic S, Sales S, Shevchenko A and Matz-Soja M (2015) RNAi in murine hepatocytes - the agony of choice. Archives of Toxicology 89, 1579-88.

Brunsch M, Schubert D, Gube M, Ring C, Hanisch L, Linde J, Krause K, Kothe E (2015) Dynein heavy chain, encoded by two genes in agaricomycetes, is required for nuclear migration in Schizophyllum commune. PLOS One 10, e0135616.

Cameron K, Tan R, Schmidt-Heck W, Cam-pos G, Lyall MJ, Wang Y, Lucendo-Villarin B, Szkolnicka D, Bates N, Kimber SJ, Hengstler JG, Godoy P, Forbes SJ, Hay DC (2015) Recombinant laminins drive the differentia-tion and self-organization of hESC-derived hepatocytes. Stem Cell Reports 5, 1250-62.

Dix A, Hünniger K, Weber M, Guthke R, Kurzai O, Linde J (2015) Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expres-sion study. Front Microbiol 6, 171.

Durmus S, Cakir T, Ozgur A, Guthke R (2015) A review on computational systems biology of pathogen-host interactions. Front Micro-biol 6, 235.

Feuer R, Vlaic S, Arlt J, Sawodny O, Dahmen U, Zanger UM, Thomas M (2015) LEMming: a linear error model to normalize parallel quantitative real-time PCR (qPCR) data as an alternative to reference gene based methods PLOS ONE 10, e0135852.

Godoy P, Schmidt-Heck W, Natarajan K, Lucendo-Villarin B, Szkolnicka D, Asplund A, Bjorquist P, Widera A, Stoeber R, Campos G, Hammad S, Sachinidis A, Damm G, Weiss TS, Nussler A, Synnergren J, Edlund K, Küp-pers-Munther B, Hay D, Hengstler JG (2015) Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J Hepatol 63, 934-42.



Horn F, Üzüm Z, Möbius N, Guthke R, Linde J, Hertweck C (2015) Draft genome se-quences of symbiotic and nonsymbiotic Rhi-zopus microsporus strains CBS 344.29 and ATCC 62417. Genome Announc 3, e01370-14.

Huyke J, Martin R, Walther G, Weber M, Kaerger K, Bougnoux ME, Elias J, Kurzai O (2015) Candida albicans bloodstream isolates in a German university hospital are genetically heterogenous and susceptible to commonly used antifungals. Int J Med Microbiol 305, 742-747.

Klassen JL, Rischer M, Wolf T, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Genome sequences of three Pseudoaltero-monas strains P1-8, P1-11 and P1-30 isolated from the marine hydroid Hydractinia echinata. Genome Announc 3, e01380-15.

Klassen JL, Wolf T, Rischer M, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Draft genome sequences of six Pseudoal-

teromonas sp. strains P1-7a, P1-9, P1-13-1a, P1-16-1b, P1-25 and P1-26, which induce larval settlement and metamorphosis in Hydractinia echinata. Genome Announc 3, e01477-15.

Kramer M, Quickert S, Sponholz C, Menzel U, Paxian M, Huse K, Platzer M, Bauer M, Claus RA (2015) Alternative splicing of SMPD1 in human sepsis. PLOS One21, e0124503.

Leonhardt I, Spielberg S, Weber M, Al-brecht-Eckardt D, Bläss M, Claus R, Barz D, Scherlach K, Hertweck C, Löffler J, Hünniger K, Kurzai O (2015) The fungal quorum-sens-ing molecule farnesol activates innate im-mune cells but suppresses cellular adaptive immunity. mBio 6, e00143.

Linde J, Duggan S, Weber M, Horn F, Sieber P, Hellwig D, Riege K, Marz M, Martin R, Guthke R, Kurzai O (2015) Defining the tran-scriptomic landscape of Candida glabrata by RNA-Seq. Nucleic Acids Res 43, 1392-1406.

Macheleidt J, Scherlach K, Neuwirth T, Schmidt-Heck W, Straßburger M, Spraker J, Baccile JA, Schroeder FC, Keller NP, Her-tweck C, Heinekamp T, Brakhage AA (2015) Transcriptome analysis of cAMP-dependent protein kinase A regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus. Mol Microbiol 96, 148-162.

Mansfeld J, Urban N, Priebe S, Groth M, Frahm C, Hartmann N, Gebauer J, Ravi-chandran M, Dommaschk A, Schmeisser S, Kuhlow D, Monajembashi S, Bremer-Streck S, Hemmerich P, Kiehntopf M, Zamboni N, Englert C, Guthke R, Kaleta C, Platzer M, Sühnel J, Witte O, Zarse K, Ristow M (2015) Branched-chain amino acid catabolism is a conserved genetic regulator of physiological aging. Nature Communications 6, 10043.

Marthandan S*, Priebe S*, Baumgart M, Groth M, Cellerino A, Guthke R, Platzer P, Hemmerich P and Diekmann S (2015) Sim-ilarities in gene expression profiles during in vitro aging of primary human embryonic lung and foreskin fibroblasts. Biomed Res Int 2015, ID 731938.

Marthandan S, Priebe S, Groth M, Guthke R, Platzer M, Hemmerich P, Diekmann S (2015) Hormetic effect of rotenone in primary hu-man fibroblasts. Immunity & Ageing 12, 11.

142

Prauße TEM, Schäuble S, Guthke R, Schus-ter S (2015) Computing the various path-ways of penicillin synthesis and their molar yields. Biotech Bioeng 113, 173-181.

Priebe S, Kreisel C, Horn F, Guthke R, Linde J (2015) FungiFun2: a comprehensive online resource for systematic analysis of gene lists from fungal species. Bioinformatics 31, 445-446.

Schmidt-Heck W, Matz-Soja M, Aleithe S, Guthke R, Gebhardt R (2015) Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes. Molecular BioSystems 11, 2190-2197.

Schulze S, Henkel SG, Driesch D, Guthke R, Linde J (2015) Computational prediction of molecular pathogen-host interactions based on dual transcriptome data. Front Microbiol 6, 65.

Shelest E, Heimerl N, Fichtner M, Sasso S (2015) Multimodular type I polyketide synthases in algae evolve by module dupli-cations and displacement of AT domains in trans. BMC genomics 16, 1015.

Sponholz C, Kramer M, Schöneweck F, Men-zel U, Inanloo Rahatloo K, Giamarellos-Bour-boulis EJ, Papavassileiou V, Lymberopoulou K, Pavlaki M, Koutelidakis I, Perdios I, Scher-ag A, Bauer M, Platzer M, Huse K (2015) Polymorphisms of cystathionine beta-syn-thase gene are associated with susceptibili-ty to sepsis. Eur J Hum Genet 24,1041-8.


Vettorazzi S, Bode C, Dejager L, Frappart L, Shelest E, Klaßen C, Tasdogan A, Reichardt HM, Libert C, Schneider M, Weih F, Uhlen-haut H, David J-P, Gräler M, Kleiman A, Tuckermann JP (2015) Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nat Commun 6, 7796.

Vlaic S, Altwasser R, Kupfer P, Nilsson CL, Emmett M, Meyer-Baese A, Guthke R (2015) Inference of Predictive Phospho-Regulatory Networks from LC-MS/MS Phosphopro-teomics Data. BIOINFORMATICS 2016 - 7 th International Conference on Bioinformatics Models, Methods and Algorithms, Proceedings; BIOSTEC 2016, 85-91.

Wagner K, Linde J, Krause K, Gube M, Koestler T, Sammer D, Kniemeyer O, Kothe E (2015) Tricholoma vaccinum host commu-nication during ectomycorrhiza formation. FEMS Microbiol Ecol 91, 11.

Wolf T, Shelest V, Nath N, Shelest E (2015) CASSIS and SMIPS: Promoter-based predic-tion of secondary metabolite gene clusters in eukaryotic genomes. Bioinformatics 32, 1138-1143.

Independent Junior Research Group Biobricks of Microbial Natural Product Syntheses

Altwasser R, Baldin C, Weber J, Guthke R, Kniemeyer O, Brakhage AA, Linde J, Valiante V (2015) Network modeling reveals cross talk of MAP kinases during adaptation to caspofungin stress in Aspergillus fumigatus. PLOS One 10, e0136932.

Baldin C, Valiante V, Krüger T, Schafferer L, Haas H, Kniemeyer O, Brakhage AA (2015) Comparative proteomics of a tor inducible Aspergillus fumigatus mutant reveals involve-ment of the Tor kinase in iron regulation. Proteomics 15, 2230-2243.

Horn F, Linde J, Mattern DJ, Walther G, Guthke R, Brakhage AA, Valiante V (2015) Draft genome sequence of the fungus Pen-icillium brasilianum MG11. Genome Announc 3, e00724-15.

Valiante V, Macheleidt J, Föge M, Brakhage AA (2015) The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence. Front Microbiol 6, 325.


Independent Junior Research Group Chemistry of Microbial Communication

Cavallari M, Stallforth P, Kalinichenko A, Rathwell DCK, Gronewold TMA, Adibekian A, Mori L, Landmann R, Seeberger PH, DeLibero G (2014) A semi-synthetic carbo-hydrate-lipid vaccine that protects against S. pneumoniae in mice. Nat Chem Biol 10, 950-956.

Stallforth P, Clardy J (2014) Atlas for drug discovery. Proc Natl Acad Sci 111, 3655-3656.

Braesel J, Götze S, Shah F, Heine D, Tauber J, Hertweck C, Tunlid A, Stallforth P, Hoffmeis-ter D (2015) Three redundant synthetases secure redox-active pigment production in the basidiomycete Paxillus involutus. Chem Biol 22, 1325-1334.

Matthies S, Stallforth P, Seeberger PH (2015) Total synthesis of legionaminic acid as basis for serological studies. J Am Chem Soc 137, 2848-2851.

Independent Junior Research Group Chemical Biology of Microbe-Host Interactions

Beemelmanns C, Woznica A, Alegado RA, Cantley AM, King N, Clardy J (2014) Synthe-sis of the rosette-inducing factor RIF-1 and analogs. J Am Chem Soc 136, 10210-10213.

Kim KH, Beemelmanns C, Murillo C, Guillén A, Umaña L, Tamayo-Castillo G., Kim SN, Clardy J, Cao, S (2014) Naphthalenones and isocoumarins from a Costa Rican fungus Xylariaceae sp. CR1546C. Journal of Chemical Research 38, 722-725.

Kim KH, Ramadhar TR, Beemelmanns C, Cao S, Poulsen M, Currie CR, Clardy J (2014) Natalamycin A, an ansamycin from a termite-associated Streptomyces sp. Chem. Sci. 5, 4333-4338.

Ramadhar TR, Beemelmanns C, Currie CR, Clardy J (2014) Bacterial symbionts in agri-cultural systems provide a strategic source for antibiotic discovery. J Antibiot 67, 53-58.

Beemelmanns C, Reissig HU (2015) Evolu-tion of a short route to strychnine by using the samarium diiodide-induced cascade cyclization as a key step. Chemistry - A Euro-pean Journal 21, 8416-8425.

Beemelmanns C, Reissig HU (2015) Strychnine as target - Samarium diiodide as


tool – A personal story. The Chemical Record 15, 872-885.

Kim KH, Beemelmanns C, Clardy J, Cao S (2015) A new antibacterial octaketide and cytotoxic phenylethanoid glycosides from Pogostemon cablin (Blanco) Benth. Bioorg Med Chem Lett 14, 2834-2836.

Klassen JL, Rischer M, Wolf T, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Genome sequences of three Pseudoaltero-monas strains P1-8, P1-11 and P1-30 isolated from the marine hydroid Hydractinia echinata. Genome Announc.3, e01380-15.

Klassen JL, Wolf T, Rischer M, Guo H, Shelest E, Clardy J, Beemelmanns C (2015) Draft genome sequences of six Pseudoal-teromonas sp. strains P1-7a, P1-9, P1-13-1a, P1-16-1b, P1-25 and P1-26, which induce larval settlement and metamorphosis in Hydractinia echinata. Genome Announc 3, e01477-15.

Independent Junior Research Group Secondary Metabolism of Predatory Bacteria

Kreutzer MF, Kage H, Herrmann J, Pauly J, Hermenau R, Müller R, Hoffmeister D, Nett M (2014) Precursor-directed biosynthesis of micacocidin derivatives with activity against Mycoplasma pneumoniae. Org Biomol Chem 12, 113-118.


Pauly J, Nett M, Hoffmeister D (2014) Ralfuranone is produced by an alternative aryl-substituted γ-lactone biosynthetic route in Ralstonia solanacearum. J Nat Prod 77, 1967-1971.

Schieferdecker S, Exner TE, Gross H, Roth M, Nett M (2014) New myxothiazols from the predatory bacterium Myxococcus fulvus. J Antibiot 67, 519-525.



Barnes EC, Bezerra-Gomes P, Nett M, Hertweck C (2015) Dandamycin and chandrananimycin E, benzoxazines from Streptomyces griseus. J Antibiot (Tokyo) 68, 463-468.

Bauer JS, Ghequire MG, Nett M, Josten M, Sahl HG, De Mot R, Gross H (2015) Biosynthetic origin of the antibiotic pseu-dopyronines A and B in Pseudomonas putida BW11M1. ChemBioChem 16, 2491-2497.

Kage H, Riva E, Parascandolo JS, Kreutzer MF, Tosin M, Nett M (2015) Chemical chain termination resolves the timing of ketore-duction in a partially reducing iterative type I polyketide synthase. Org Biomol Chem 13, 11414-11417.

Korp J, König S, Schieferdecker S, Dahse HM, König G M, Werz O, Nett M (2015) Harnessing enzymatic promiscuity in myxochelin biosynthesis for the production of 5-lipoxygenase inhibitors. ChemBioChem 16, 2445-2450.

Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Mo-rales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escriba-no JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-

Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O‘Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11, 625-631.

Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and absolute configuration of auriculamide, a natural product from the predatory bac-terium Herpetosiphon aurantiacus. Eur J Org Chem 14, 3057-3062.

Schieferdecker S, König S, Koeberle A, Dahse HM, Werz O, Nett M (2015) Myxoche-lins target human 5-lipoxygenase. J Nat Prod 78, 335-338.

Seccareccia I, Kost C, Nett M (2015) Quanti-tative analysis of Lysobacter predation. Appl Environ Microbiol 81, 7098-7105.

Cross-sectional Unit Bio Pilot Plant

Heine D, Martin K, Hertweck C (2014) Genomics-guided discovery of en-dophenazines from Kitasatospora sp. HKI 714. J Nat Prod 77, 1083-1087.


Kämpfer P, Dott W, Martin K, Glaeser SP (2014) Rhodococcus defluvii sp. nov., isolated from wastewater of a bioreactor and formal proposal to reclassify [Corynebacterium hoagii] and Rhodococcus equi as Rhodococ-cus hoagii comb. nov. Int J Syst Evol Microbiol 64, 755-761.

Kroll K, Pähtz V, Hillmann F, Vaknin Y, Schmidt-Heck W, Roth M, Jacobsen ID, Os-herov N, Brakhage AA, Kniemeyer O (2014) Identification of hypoxia-inducible target genes of Aspergillus fumigatus by transcrip-tome analysis reveals cellular respiration as

144

important contributor to hypoxic survival. Eukaryot Cell 13, 1241-1253.

Lüdecke C, Jandt KD, Siegismund D, Kujau MJ, Zang E, Rettenmayr M, Bossert J, Roth M (2014) Reproducible biofilm cultivation of chemostat-grown Escherichia coli and investigation of bacterial adhesion on bio-materials using a non-constant-depth film fermenter. PLOS One 9, e84837.


Pidot S, Ishida K, Cyrulies M, Hertweck C (2014) Discovery of clostrubin, an exception-al polyphenolic polyketide antibiotic from a strictly anaerobic bacterium. Angew Chem Int Ed 53, 7856-7859.

Schieferdecker S, Exner TE, Gross H, Roth M, Nett M (2014) New myxothiazols from the predatory bacterium Myxococcus fulvus. J Antibiot 67, 519-525.

Schmitz A, Kehraus S, Schäberle TF, Neu E, Almeida C, Roth M, König GM (2014) Corallorazines from the myxobacterium Corallococcus coralloides. J Nat Prod 77(1), 159-163.

Schütze E, Ahmed E, Voit A, Klose M, Greyer M, Svatoš A, Merten D, Roth M, Holmström SJ, Kothe E (2014) Siderophore production by streptomycetes-stability and alteration of ferrihydroxamates in heavy metal-con-taminated soil. Environ Sci Pollut Res Int 22, 19376-19383.

Schütze E, Klose M, Merten D, Nietzsche S, Senftleben D, Roth M, Kothe E (2014) Growth of streptomycetes in soil and their impact on bioremediation. J Hazard Mater 267, 128-135.

Schwenk D, Nett M, Dahse H-M, Horn U, Blanchette RA, Hoffmeister D (2014) Inju-ry-induced biosynthesis of methyl-branched polyene pigments in a white-rotting basidio-mycete. J Nat Prod 77, 2658-2663.

Wacker J, Rönicke R, Westermann M, Wulff M, Reymann KG, Dobson CM, Horn U, Crowther DC, Luheshi LM, Fändrich M (2014) Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. Acta Neuropathol Com-mun 2, 43.

Wink J, Schumann P, Spöer C, Eisenbarth K, Glaeser SP, Martin K, Kämpfer P (2014) Emended description of Actinoplanes friuliensis and description of Actinoplanes nipponensis sp. nov., antibiotic-producing species of the genus Actinoplanes. Int J Syst Evol Microbiol 64, 599-606.

Baunach M, Ding L, Willing K, Hertweck C (2015) Bacterial synthesis of unusual sulfonamide and sulfone antibiotics by fla-voenzyme-mediated sulfur dioxide capture. Angew Chem Int Ed 54, 13279-13283.

Elschner T, Lüdecke C, Kalden D, Roth M, Löffler B, Jandt KD, Heinze T (2015) Zwitteri-onic cellulose carbamate with regioselective substitution pattern: a coating material possessing antimicrobial activity. Macromol Biosci 16, 522-534.

Kämpfer P, Martin K, McInroy JA, Glaeser SP (2015) Proposal of Novosphingobium rhizo- sphaerae sp. nov., isolated from the rhizo-sphere. Int J Syst Evol Microbiol 65, 195-200.

Mahler L, Tovar M, Weber T, Brandes S, Rudolph MM, Ehgartner J, Mayr T, Figge MT, Roth M, Zang E (2015) Enhanced and homogeneous oxygen availability during incubation of microfluidic droplets. RSC Advances 5, 101871-101878.

Phieler R, Merten D, Roth M, Büchel G, Kothe E (2015) Phytoremediation using microbially mediated metal accumulation in Sorghum bi-color. Environ Sci Pollut Res 22, 19408-19416.

Schäberle TF, Schmitz A, Zocher G, Schiefer A, Kehraus S, Neu E, Roth M, Vassylyev DG, Stehle T, Bierbaum G, Hoerauf A, Pfarr K, König GM (2015) Insights into structure

– Activity relationships of bacterial RNA poly-merase inhibiting corallopyronin derivatives. J Nat Prod 78, 2505-2509.

Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and absolute configuration of auriculamide, a natural product from the predatory bac-terium Herpetosiphon aurantiacus. Eur J Org Chem 14, 3057-3062.

Shabuer G, Ishida K, Pidot SJ, Roth M, Dahse HM, Hertweck C (2015) Plant pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory. Science 350, 670-674.

van Dissel D, Claessen D, Roth M, van Wezel GP (2015) A novel locus for mycelial

aggregation forms a gateway to improved Streptomyces cell factories. Microb Cell Fact, 14, 44.

Cross-sectional Unit JMRC – Jena Microbial Resource Collection

de A. Santiago ALCM , Hoffmann K, Lima DX, de Oliveira RJV, Vieira HEE, Malosso E, Maia LC, da Silva GA (2014) A new species of Lichtheimia (Mucoromycotina, Mucorales) isolated from Brazilian soil. Mycol Progress 13, 343-352.

Grützmann K, Szafranski K, Pohl M, Voigt K, Petzold A, Schuster S (2014) Fungal alterna-tive splicing is associated with multicellular complexity and virulence: a genome-wide multi-species study. DNA Res 21, 27-39.


Linde J, Schwartze V, Binder U, Lass-Flörl C, Voigt K, Horn F (2014) De novo whole-ge-nome sequence and genome annotation of Lichtheimia ramosa. Genome Announc 2, e00888-14.

Mendoza L, Vilela R, Voelz K, Ibrahim AS, Voigt K, Lee SC (2014) Human fungal patho-gens of mucorales and entomophthorales. Cold Spring Harb Perspect Med 5, Chapter 27.


Schwartze VU, de A. Santiago ALCM, Jacobsen ID, Voigt K (2014) The pathogenic potential of the Lichtheimia genus revisited: Lichtheimia brasiliensis is a novel, non-patho-genic species. Mycoses 57, Suppl. 3, 128-131.


Schwartze VU, Winter S, Shelest E, Marcet-Houben M, Horn F, Wehner S, Linde J, Valiante V, Sammeth M, Riege K, Nowrou-sian M, Kaerger K, Jacobsen ID, Marz M, Brakhage AA, Gabaldón T, Böcker S,


Voigt K (2014) Gene expansion shapes genome architecture in the human pathogen Lichtheimia corymbifera: an evolutionary genomics analysis in the ancient terrestrial Mucorales (Mucoromycotina). PLOS Genetics 10, e1004496.

Ariyawansa HA, Hyde KD, Jayasiri SC, Buyck B, Chethana KWT, Dai DQ, Dai YC, Daranag-ama DA, Jayawardena RS, Lücking R, Ghobad-Nejhad M, Niskanen T, Thambugala KM, Voigt K, Rui Lin Zhao and the fungal diversity consortium (2015) Fungal diversity notes 111-252 – taxonomic and phyloge-netic contributions to fungal taxa. Fungal Diversity 75, 27-274.


Münchberg U, Wagner L, Rohrer C, Voigt K, Rösch P, Jahreis G, Popp J (2015) Quan-titative assessment of the degree of lipid unsaturation in intact mortierella by raman microspectroscopy. Anal Bioanal Chem 407, 3303-3311.

Associated Group Infections in Hematology / Oncology

Busch A, Zeh D, Janzen V, Mügge LO, Wolf D, Fingerhut L, Hahn-Ast C, Maurer O, Brossart P, von Lilienfeld-Toal M (2014) Treatment with lenalidomide induces immunoactivat-ing and counter-regulatory immunosuppres-sive changes in myeloma patients. Clin Exp Immunol 177, 439-453.

Penack O, Becker C, Buchheidt D, Christopeit M, Kiehl M, von Lilienfeld-Toal M, Hentrich M, Reinwald M, Salwender H, Schalk E, Schmidt-Hieber M, Weber T, Ostermann H (2014) Management of sepsis in neutrope-nic patients: 2014 updated guidelines from the Infectious diseases working party of the German Society of Hematology and Medical Oncology (AGIHO). Ann Hematol 93, 1083-1095.

Schwab KS, Hahn-Ast C, Heinz WJ, Germing U, Egerer G, Glasmacher A, Leyendecker C, Marklein G, Nellessen CM, Brossart P, von Lilienfeld-Toal M (2014) Tigecycline in febrile neutropenic patients with haemato-

logical malignancies: a retrospective case documentation in four university hospitals. Infection 42, 97-9104.

Vehreschild MJ, Hamprecht A, Peterson L, Schubert S, Häntschel M, Peter S, Schaf-hausen P, Rohde H, von Lilienfeld-Toal M, Bekeredjian-Ding I, Libam J, Hellmich M, Vehreschild JJ, Cornely OA, Seifert H (2014) A multicentre cohort study on coloniza-tion and infection with ESBL-producing Enterobacteriaceae in high-risk patients with haematological malignancies. J Antimicrob Chemother 69, 3387-3392.

Mayer K, Hahn-Ast C, Mückter S, Schmitz A, Krause S, Felder L, Bekeredjian-Ding I, Molitor E, Brossart P, von Lilienfeld-Toal M (2015) Comparison of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia. Support Care Cancer 23, 1321-1329.

Sandherr M, Hentrich M, von Lilienfeld-Toal M, Massenkeil G, Neumann S, Penack O, Biehl L, Cornely OA (2015) Antiviral prophy-laxis in patients with solid tumours and haematological malignancies-update of the guidelines of the infectious diseases work-ing party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Hematol 94, 1441-1450.

Schnetzke U, Spies-Weisshart B, Yomade O, Fischer M, Rachow T, Schrenk K, Glaser A, von Lilienfeld-Toal M, Hochhaus A, Scholl S (2015) Polymorphisms of toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16, 83-88.

Schrenk KG, Schnetzke U, Stegemann K, von Lilienfeld-Toal M, Hochhaus A, Scholl S (2015) Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia. J Cancer Res Clin Oncol 141, 1661-1668

Associated Group Microbial Biochemistry and Physiology

Brunke S, Seider K, Richter ME, Bremer-Streck S, Ramachandra S, Kiehntopf M, Brock M, Hube B (2014) Histidine degra-dation via an aminotransferase increases the nutritional flexibility of Candida glabrata. Eukaryot Cell 13, 758-765.



Ramachandra S, Linde J, Brock M, Guthke R, Hube B, Brunke S (2014) Regulatory networks controlling nitrogen sensing and uptake in Candida albicans. PLOS One 9, e92734.

Zaehle C, Gressler M, Shelest E, Geib E, Hert-weck C, Brock M (2014) Terrein biosynthesis in Aspergillus terreus and its impact on phytotoxicity. Chem Biol 21, 719-731.

Gressler M, Hortschansky P, Geib E, Brock M (2015) A new high-performance heterol-ogous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front Microbiol 6, 184.


Associated Group Network Modeling

Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, Milde T, Bourdeaut F, Ryzhova M, Sturm D, Pfaff E, Stark S, Hutter S, Seker-Cin H, Johann P, Bender S, Schmidt C, Rausch T, Shih D, Reimand J, Sieber L, Wittmann A, Linke L, Witt H, Weber UD, Zapatka M, König R, Beroukhim R, Bergthold G, van Sluis P, Volckmann R, Koster J, Versteeg R, Schmidt S, Wolf S, Lawerenz C, Bartholomae CC, von Kalle C, Unterberg A, Herold-Mende C, Hofer S, Kulozik AE, von Deimling A, Scheurlen W, Felsberg J, Reifenberger G, Hasselblatt M, Crawford JR, Grant GA, Jabado N, Perry A, Cowdrey C, Croul S, Zadeh G, Korbel JO, Doz F, Delattre O, Bader GD, McCabe MG, Collins VP, Kieran MW, Cho YJ, Pomeroy SL, Witt O, Brors B, Taylor MD, Schüller U, Korshunov A, Eils R, Wechsler-Reya RJ, Lichter P, Pfister

146

SM (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25, 393-405.

Piro RM, Wiesberg S, Schramm G, Rebel N, Oswald M, Eils R, Reinelt G, König R (2014) Network topology-based detection of differential gene regulation and regulatory switches in cell metabolism and signaling. BMC Syst Biol 8, 56.

Schacht T, Oswald M, Eils R, Eichmüller SB, König R (2014) Estimating the activity of transcription factors by the effect on their target genes. Bioinformatics 30, i401-i407.

Sonntag J, Bender C, Soons Z, Aulmann S, von der Heyde S, Nietert M, Lier A, König R, Wiemann S, Beißbarth T, Sinn HP, Schnee-weiss A, Korf U (2014) Reverse phase protein array based tumor profiling identifies a biomarker signature for risk classification of hormone receptor-positive breast cancer. Trans Proteomics 2, 52-59.

Suratanee A, Schaefer MH, Betts MJ, Soons Z, Mannsperger H, Harder N, Oswald M, Gipp M, Ramminger E, Marcus G, Männer R, Rohr K, Wanker E, Russell RB, Andrade-Navarro MA, Eils R, König R (2014) Characterizing Protein Interactions Employing a Ge-nome-Wide siRNA Cellular Phenotyping Screen. PLOS Comput Biol 10, e1003814.

Ummanni R, Mannsperger HA, Sonntag J, Oswald M, Sharma AK, König R, Korf U (2014) Evaluation of reverse phase protein array (RPPA)-based pathway-activation profiling in 84 non-small cell lung cancer (NSCLC) cell lines as platform for cancer proteomics and biomarker discovery. Bio-chim Biophys Acta 1844, 950-959.

Ward A, Shukla K, Balwierz A, Soons Z, König R, Sahin O, Wiemann S (2014) Mi-croRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer. J Pathol 233, 368-379.

Harder N, Batra R, Diessl N, Gogolin S, Eils R, Westermann F, König R, Rohr K (2015) Large-scale tracking and classification for automatic analysis of cell migration and pro-liferation, and experimental optimization of high-throughput screens of neuroblastoma cells. Cytometry A 87, 524-540.

Khandelwal N, Breinig M, Speck T, Michels T, Kreutzer C, Sorrentino A, Sharma AK, Uman-sky L, Conrad H, Poschke I, Offringa R, König R, Bernhard H, Machlenkin A, Boutros M, Beckhove P (2015) A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes. EMBO Mol Med 7, 450-463.

Shukla K, Sharma AK, Ward A, Will R, Hielscher T, Balwierz A, Breunig C, Münster-mann E, König R, Keklikoglou I, Wiemann S (2015) MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle pro-gression through downregulation of TRADD and CCNE1 in breast cancer. Mol Oncol 9, 1106-1119.

Stark H, Fichtner M, König R, Lorkowski S, Schuster S (2015) Causes of upregulation of glycolysis in lymphocytes upon stimula-tion. A comparison with other cell types. Biochimie 118, 185-194.

Associated Group Pharmaceutical Microbiology

Benoit I, van den Esker MH, Patyshakuliyeva A, Mattern DJ, Blei F, Zhou M, Dijksterhuis J, Brakhage AA, Kuipers OP, de Vries RP, Kovács AT (2014) Bacillus subtilis attach-ment to Aspergillus niger hyphae results in mutually altered metabolism. Environ Microbiol 17, 2099-2113.


Bohnert M, Scherer O, Wiechmann K, König S, Dahse HM, Hoffmeister D, Werz O (2014) Melleolides induce rapid cell death in human primary monocytes and cancer cells. Bioorg Med Chem 22, 3856-3861.

Chankhamjon P, Boettger-Schmidt D, Scher-lach K, Urbansky B, Lackner G, Kalb D, Dahse HM, Hoffmeister D, Hertweck C (2014) Biosynthesis of the halogenated my-cotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion. Angew Chem Int Ed 53, 13409-13413.

Hori C, Ishida T, Igarashi K, Samejima M, Su-zuki H, Master E, Ferreira P, Ruiz-Dueñas FJ, Held B, Canessa P, Larrondo LF, Schmoll M,

Druzhinina IS, Kubicek CP, Gaskell JA, Ker-sten P, St John F, Glasner J, Sabat G, Splinter BonDurant S, Syed K, Yadav J, Mgbeahurui-ke AC, Kovalchuk A, Asiegbu FO, Lackner G, Hoffmeister D, Rencoret J, Gutiérrez A, Sun H, Lindquist E, Barry K, Riley R, Grigoriev IV, Henrissat B, Kües U, Berka RM, Martínez AT, Covert SF, Blanchette RA, Cullen D (2014) Analysis of the Phlebiopsis gigantea genome, transcriptome and secretome provides in-sight into its pioneer colonization strategies of wood. PLOS Genet 10, e1004759.

Kalb D, Lackner G, Hoffmeister D (2014) Functional and phylogenetic divergence of fungal adenylate-forming reductases. Appl Environ Microbiol 80, 6175-6183.

Kreutzer MF, Kage H, Herrmann J, Pauly J, Hermenau R, Müller R, Hoffmeister D, Nett M (2014) Precursor-directed biosynthesis of micacocidin derivatives with activity against Mycoplasma pneumoniae. Org Biomol Chem 12, 113-118.

Pauly J, Nett M, Hoffmeister D (2014) Ralfuranone is produced by an alternative aryl-substituted γ-lactone biosynthetic route in Ralstonia solanacearum. J Nat Prod 77, 1967-1971.


Braesel J, Götze S, Shah F, Heine D, Tauber J, Hertweck C, Tunlid A, Stallforth P, Hoffmeister D (2015) Three redundant synthetases secure redox-active pigment production in the basidiomycete Paxillus involutus. Chem Biol 22, 1325-1334.


Kalb D, Lackner G, Rappe M, Hoffmeister D (2015) Activity of α-aminoadipate reductase depends on the N-terminally extending domain. Chembiochem 16, 1426-1430.

Karlsson M, Durling MB, Choi J, Kosawang C, Lackner G, Tzelepis GD, Nygren K, Dubey MK, Kamou N, Levasseur A, Zapparata A, Wang J, Amby DB, Jensen B, Sarrocco S,


Panteris E, Lagopodi AL, Pöggeler S, Van-nacci G, Collinge DB, Hoffmeister D, Henris-sat B, Lee YH, Jensen DF (2015) Insights on the evolution of mycoparasitism from the genome of Clonostachys rosea. Genome Biol Evol 7, 465-480.

Stadler M, Hoffmeister D (2015) Fungal natural products-the mushroom perspective. Front Microbiol 6, 127.

148

REVIEWS, MONOGRAPHS, BOOK CHAPTERSÜBERSICHTSARBEITEN, MONOGRAPHIEN, SAMMELWERKE

Department Biomolecular Chemistry

Crews C, Hertweck C, Shokat K, Suga H, Kostic M (2014) Reflecting on the past and looking forward to the future of bridging chemistry and biology. Chem Biol 21, 1035-1036.

Baunach M, Hertweck C (2015) Natural 1,3-Dipolar Cycloadditions. Angew Chem Int Ed 54, 12550-12552.

Hertweck C (2015) Decoding and repro-gramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci. 40, 189-199.

Hertweck C (2015) Natural products as source of therapeutics against parasitic dis-eases. Angew Chem Int Ed 54, 14622-14624.

Department Infection Biology

Zipfel PF, Skerka C (2014) Staphylococcus aureus: the multi headed hydra resists and controls human complement response in multiple ways. Int J Med Microbiol 304, 188-194.

Zipfel PF, Skerka C (2015) Complement: The alternative pathway. eLS. 1-10.

Department Microbial Pathogenicity Mechanisms

Fischer D, Hube B, Brunke S (2014) Fine-scale chromosomal changes in fungal fitness. J Curr Fungal Infect Rep, 8, 171-178.

Hebecker B, Naglik JR, Hube B, Jacobsen ID (2014) Pathogenicity mechanisms and host response during oral Candida albicans infec-tions. Expert Rev Anti Infect Ther 12, 867-879.

Hube B (2014) Clotrimazol bei C. albicans-In-fektionen. Dem Wirkmechanismus auf der Spur. Frauenarzt, Apr 14, 370-372.

Whittington A, Gow NAR, Hube B (2014) From commensal to pathogen: Candida albicans. In: Esser K, Kurzai O (eds.) The My-cota Ed. 2. Vol. XII, pp. 3-18. Springer Verlag, Berlin, Heidelberg, Germany.

Cavet JS, Perry RD, Brunke S, Darwin KH, Fierke CA, Imlay JA, Murphy M, Schryvers AB, Thiele DJ, Weiser JN (2015) Metal ions in host microbe interactions: The microbe perspective. In: Nriagu JO, Skaar EP (eds.) Trace Metals and Infectious Diseases. The MIT Press. Strüngmann Forum Reports. Cambridge, USA.

Hube B (2015) Virulence profile: Bernhard Hube. Virulence 6, 523-525. (Review).

Polke M, Hube B, Jacobsen ID (2015) Candi-da survival strategies. Adv Appl Microbiol 91, 139-235.

Department Molecular and Applied Microbiology

Benny GL, Humber RA, Voigt K (2014) The zygomycetous Fungi: The phylum Entomoph-thoromycota and the subphyla Kickxellomy-cotina, Mortierellomycotina, Mucoromycotina, and Zoopagomycotina. In: McLaughlin DJ, Blackwell M, Spatafora JW (eds.) The Mycota Vol. VIIA: Systematics of fungi. pp. 209-250. Springer Verlag, Berlin, Heidelberg, New York.

Heinekamp T, Valiante V, Koester-Eiser-funke N, Brakhage AA (2014) Functional genomics to characterize opportunistic pathogens. In: Nowrousian M (ed.) The Mycota Vol. XIII: Fungal Genomics. pp. 321-347. Springer Verlag, Berlin, Heidelberg, New York.

Horn F, Valiante V, Guthke R, Brakhage AA (2014) Data-driven systems biology of fungal infections. In: Sullivan D, Moran GP (eds.) Human pathogenic Fungi: Molecular biology and pathogenic mechanisms. Caister Aca-demic Press, Norfolk, U.K.

Mendoza L, Vilela R, Voelz K, Ibrahim AS, Voigt K, Lee SC (2014) Human fungal patho-gens of mucorales and entomophthorales. Cold Spring Harb Perspect Med 5, Chapter 27, pii: a019562.

Scharf DH, Heinekamp T, Brakhage AA (2014) Human and plant fungal pathogens:

the role of secondary metabolites. PLOS Pathog 10, e1003859.

Schroeckh V, Nützmann HW, Brakhage AA (2014) Fungal-actinomycete interactions – wakening of silent fungal secondary me-tabolism gene clusters via interorganismic interactions. In: Osbourn A, Goss RJ, Carter GT (eds.) Natural Products: Discourse, Diver-sity, and Design pp. 147-158. John Wiley & Sons, Inc., Hoboken, USA.

Shelest E, Voigt K (2014) Genomics to study basal lineage fungal biology: phylogenomics suggest a common origin. In: Alistair J.B. Brown (ed.) The Mycota XIII, Fungal Genom-ics 2. edition. 13, pp. 31-60. Springer, Berlin, Heidelberg.

Voigt K, Kirk PM (2014) Classification of the Zygomycetes. In: Batt CA, Tortorello ML (eds.) Encyclopedia of Food Microbiology 2nd edition. pp. 54-67. Elsevier. London, UK

Ariyawansa HA, Hyde KD, Jayasiri SC, Buyck B, Chethana KWT, Dai DQ, Dai YC, Daranagama DA, Jayawardena RS, Lücking R, Ghobad-Nejhad M, Niskanen T, Thambu-gala KM, Voigt K, Zhao RL and the fungal diversity consortium (2015) Fungal diversity notes 111–252 - taxonomic and phylogenetic contributions to fungal taxa. Fungal Diversity 75, 27-274.

Fliegerová K, Kaerger K, Kirk PM, Voigt K (2015) Rumen fungi. In: Puniya AK, Singh R, Kamra DN (eds.) Rumen Microbiology: From Evolution to Revolution Chapter 7, pp. 97-112. Springer New Dehli, New Delhi, Heidelberg, New York, Dordrecht, London.

Heinekamp T, Schmidt H, Lapp K, Pähtz V, Shopova I, Köster-Eiserfunke N, Krüger T, Kniemeyer O, Brakhage AA (2015) Interference of Aspergillus fumigatus with the immune response. Semin Immunopathol 37, 141-152.

Krüger T, Luo T, Schmidt H, Shopova I, Kniemeyer O (2015) Challenges and strat-egies for proteome analysis of the interac-tion of human pathogenic fungi with host immune cells. Proteomes 3, 467-495.


Mattern DJ, Valiante V, Unkles SE, Brakhage AA (2015) Synthetic biology of fungal natural products. Front. Microbiol. 6, 775.

Netzker T, Fischer J, Weber J, Mattern DJ, König CC, Valiante V, Schroeckh V, Brakhage AA (2015) Microbial communica-tion leading to the activation of silent fungal secondary metabolite gene clusters. Front Microbiol 6, 299.

Valiante V, Macheleidt J, Föge M, Brakhage AA (2015) The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence. Front Microbiol 6, 325.

Department Cell and Molecular Biology

Knittler MR, Berndt A, Böcker S, Dutow P, Hänel F, Heuer D, Hennersdorf P, Kägebein D, Klos A, Koch S, Liebler-Tenorio E, Ostermann C, Reinhold P, Saluz HP, Schöfl G, Sehnert P, Sachse K (2014) Chlamydia psittaci: New insights into genomic diversity, clinical pathology, host-pathogen interaction and anti-bacterial immunity. Int J Med Microbiol 304, 877-893.

Research Group Fungal Septomics

Duggan S, Leonhardt I, Hünniger K, Kurzai O (2015) Host response to Candida albicans bloodstream infection and sepsis. Virulence 6, 316-26.

Research Group Microbial Immunology

Jacobsen ID (2014) Galleria mellonella as a model host to study virulence of Candida. Virulence 5, 237-239.

Research Group Systems Biology and Bioinformatics


Sasso S, Shelest E, Hoffmeister D (2014) Comments on the distribution and phyloge-ny of type I polyketide synthases and nonri-bosomal peptide synthetases in eukaryotes. Proc Natl Acad Sci 111, E3946.


Linde J, Schulze S, Henkel SG, Guthke R (2015) Data- and knowledge-based modeling of gene regulatory networks: An update. EXCLI Journal 14, 346-378.

Schleicher J, Conrad T, Gustafsson M, Ced-ersund G, Guthke R, Linde J (2015) Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interac-tions. Briefings in Functional Genomics 2016, elv064.

Independent Junior Research Group Biobricks of Microbial Natural Product Syntheses

Heinekamp T, Valiante V, Koester-Eiserfunke N, Brakhage AA (2014) Functional genomics to characterize opportunistic pathogens. In: Nowrousian M (ed.) The Mycota Vol. XIII: Fungal Genomics. pp. 321-347. Springer Verlag, Berlin, Heidelberg, New York.


Independent Junior Research Group Sec-ondary Metabolism of Predatory Bacteria

Nett M (2014) Genome mining – concept and strategies for natural product discovery. Prog Chem Org Nat Prod 99, 199-245.

Cross-sectional Unit Jena Microbial Resource Collection

Benny GL, Humber RA, Voigt K (2014) The zygomycetous Fungi: The phylum Entomoph-thoromycota and the subphyla Kickxellomy-cotina, Mortierellomycotina, Mucoromycotina, and Zoopagomycotina. In: McLaughlin DJ, Blackwell M, Spatafora JW (eds.) The Mycota Vol. VIIA: Systematics of fungi. 2nd edition. pp. 209-250. Springer Verlag, Berlin, Heidelberg, New York.

de Hoog S, Ibrahim AS, Voigt K (2014) Zygo-mycetes: an emerging problem in the clinical laboratory. Mycoses 57, Suppl. 3, 1.

El-Shabrawi MH, Kamal NM, Kaerger K, Voigt K (2014) Diagnosis of gastrointestinal basidiobolomycosis: a mini-review. Mycoses 57, Suppl. 3, 138-143.

Fliegerová K, Kaerger K, Kirk PM, Voigt K (2015) Rumen fungi. In: Puniya AK, Singh R, Kamra DN (eds.) Rumen Microbiology: From Evolution to Revolution Chapter 7, pp. 97-112. Springer New Dehli, New Delhi, Heidelberg, New York, Dordrecht, London.

Park HR, Voigt K (2014) Interaction of Zygomycetes with innate immune cells reconsidered with respect to ecology, mor-phology, evolution and infection biology: a mini-review. Mycoses 57, Suppl. 3, 31-39.


Schwartze VU, Hoffmann K (2015) Lichtheimia (ex Absidia). In: Russell R, Pater-son M, Lima N (eds.) Molecular biology of food and water borne mycotoxigenic and mycotic fungi, pp. 355-374. CRC Press Inc, Boca Raton, USA.

Associated Group Microbial Biochemistry and Physiology

Papon N, Courdavault V, Lanoue A, Clastre M, Brock M (2014) Illuminating fungal infec-tions with bioluminescence. PLOS Pathog 10, e1004179.

Brock M (2015) Bringing light into the dark site of infection. Cytometry Part A. 87, 793-794.

Associated Group Pharmaceutical Microbiology

Sasso S, Shelest E, Hoffmeister D (2014) Comments on the distribution and phyloge-ny of type I polyketide synthases and nonri-bosomal peptide synthetases in eukaryotes. Proc Natl Acad Sci 111, E3946.

150

MEMBERSHIPS IN EDITORIAL BOARDSMITGLIEDSCHAFTEN IN EDITORIAL BOARDS

Brakhage, Axel A. Frontiers in Microbiology/Fungi and their Interaction Applied and Environmental Microbiology Current Genetics Applied Microbial Biotechnology eLife Molecular Microbiology

Brock, Matthias FEMS Microbiology Letters Pathogens

Cseresnyes, Zoltan ScienceOpen

Figge, Marc Thilo Cytometry Part A, Special Issue “Image-based Systems Biology” FIAS Interdisciplinary Science Series, Springer Int. Publishing Frontiers in Physics Journal of Computational Medicine ISRN Biomathematics ISRN Computational Biology Computational and Mathematical Methods in Medicine

Guthke, Reinhard BMC Systems Biology Frontiers Microbiology

Hallström, Teresia Frontiers in Molecular Innate Immunity

Hertweck, Christian Chemistry & Biology Organic & Biomolecular Chemistry The Journal of Antibiotics Bio-organic Chemistry ChemBioChem

Hillmann, Falk Frontiers in Microbiology

Hoffmeister, Dirk Applied and Environmental Microbiology Fungal Diversity Mycological Progress

Horn, Uwe Microbiological Research

Hube, Bernhard BMC Microbiology Cellular Microbiology FEMS Yeast Research Pathogens Frontiers in Microbiology Frontiers in Immunology mBio Current Medical Mycology Microbiology

Jacobsen, Ilse Medical Mycology Case Reports PLOS One

Kniemeyer, Olaf Archives of Microbiology PLOS ONE Frontiers in Microbiology

Kurzai, Oliver Medical Mycology Case Reports

Linde, Jörg Frontiers Microbiology Frontiers Genetics

Nett, Markus Archives of Microbiology

Saluz, Hans Peter BioMethods

Shelest, Ekaterina Frontiers in Genetics

Valiante, Vito Frontiers in Microbiology

Voigt, Kerstin Journal of Basic Microbiology Acta Biologica Szegediensis MycoKeys

Zipfel, Peter F. Molecular Immunology Frontiers in Immunology


LECTURES AT THE HKI KOLLOQUIEN AM HKI

2014

Müller, Rolf Helmholtz-Institute for Pharmaceutical Sci-ences (HIPS), Saarland University, Germany Natural Product Research at the HIPS – Dis-covery of novel compounds from myxobac-teria 06.02.2014

Weiberg, Arne University of California, USA Fungal small RNAs suppress plant immunity by hijacking host RNAi pathway 25.04.2014

Peter, Hans-Hartmut University of Freiburg, Germany Autoimmunity, infections and immunodefi-ciencies 18.07.2014

Huber-Lang, Markus University of Ulm, Germany Complement in sepsis – Tip of the Balance? 18.07.2014

Schwaneberg, Ulrich RWTH Aachen University, Germany Protein engineering for biocatalysis and interactive materials 26.11.2014

Stadler, Marc Helmholtz Centre for Infection Research, Braunschweig, Germany New bioactive secondary metabolites from cultures of Asian edible mushrooms and tropical basidiomycetes 02.12.2014

Fischbach, Michael University of California, USA Insights from a global view of secondary metabolism: Small molecules from the human microbiota 02.12.2014

Schweder, Thomas University of Greifswald, Germany Heterologous expression of biosynthetic

gene clusters in Bacillus subtilis 02.12.2014

Wiechert, Wolfgang Forschungszentrum Jülich, Germany What bioengineers can do for biology: bioreactors in the “omics” age 02.12.2014

Thines, Eckhard Johannes Gutenberg University Mainz, Germany Fungal secondary metabolites from plant pathogenic fungi and their impact on plant/ pathogen-interactions 02.12.2014

Neubauer, Peter Technical University of Berlin, Germany Combined cell and bioprocess engineering strategies for reconstitution of valinomycin production in Escherichia coli 02.12.2014

2015

Freitag, Michael Oregon State University, USA Chromatin structure controls expression of secondary metabolism 29.01.2015

Kley, Ernst-Bernhard Friedrich Schiller University Jena, Germany Micro- and nanostructured optics, its application and its perspectives for the life sciences 17.02.2015

Ligeti, Erzsébet Semmelweis University, Budapest, Hungary Formation and biological role of extracellular vesicles from neutrophilic granulocytes 16.04.2015

Kayser, Oliver Technical University Dortmund, Germany Production of tetrahydrocannabinolic acid – from biotransformation to biotechnology 20.05.2015

Liu, Xinyu University of Pittsburgh, USA Nonheme iron enzyme mediated function-alization of unactivated carbon centers in complex alkaloid biogenesis 25.06.2015

Hochgräfe, Falko University of Greifswald, Germany PTMomics in host-pathogen-interactions 13.10.2015

Busscher, Henk J. University of Groningen, The Netherlands Nanoscopic vibrations of bacteria adhering to surfaces and their relevance for adhesion and detachment 17.11.2015

Ren, Yijin Friedrich Schiller University Jena, Germany Micro- and nanostructured optics, its application and its perspectives for the life sciences 17.11.2015

Lackner, Gerald ETH Zürich, Switzerland Polyketide and peptide biosynthesis in symbiotic and pathogenic microbes 10.07.2015

Kries, Hajo John Innes Centre, Norwich, UK Tailor-made natural product synthetases 03.06.2015

Cedersund, Gunnar Linköping University, Sweden Multi-scale and multi-resolution models as an integrated tool in experimental biology: applications to diabetes and its complica-tions 04.05.2015

152

MEETINGS, WORKSHOPS, SYMPOSIAWISSENSCHAFTLICHE VERANSTALTUNGEN

2014

2nd International Workshop Image-based Systems Biology I2b0S1B4 Figge, Marc Thilo; Guthke, Reinhard Jena, Germany

4th International Student Conference on microbial communication (MiCom 2014) Park, Hea Reung; Schmidt, Hella; Seccareccia, Ivana; Üzüm, Zerrin; Wolf, Thomas Jena, Germany

Irseer Naturstofftage Hertweck, Christian Irsee, Germany

Symposium Biotechnology of Natural Products Brakhage, Axel A. Jena, Germany

Workshop „Antibiotics: Limitations in Development?” Gemeinsamer Workshop von InfectControl 2020, der Nationalen Akademie der Wissenschaften Leopoldina und der Akademie der Wissenschaften in Hamburg Brakhage, Axel A. Halle, Germany

2015

5th International Student Conference on microbial communication (MiCom 2015) Braga de Lima, Daniel; Saraiva Joao Jena, Germany

28th Fungal Genetics Conference: Concurrent ses-sion: In vivo Imaging of Host-pathogen Interactions Brock, Matthias Asilomar, CA, USA

49th Wissenschaftliche Tagung der Deutschsprachi-gen Mykologischen Gesellschaft (DMYKG) 1st Inter-national Symposium of the CRC/Transregio FungiNet Brakhage, Axel A.; Figge, Marc Thilo; Kurzai, Oliver Jena, Germany

Gordon Research Conference & Gordon Research Seminar: Immunology of Fungal Infections Hube, Bernhard Galveston, USA

International Congress on Systems Immunology, Immunoinformatics & Immune-computation ICSI3 Figge, Marc Thilo Taormina, Italy

Invasive Mycoses in Hematological Malignancies IX Kurzai, Oliver Würzburg, Germany

Irseer Naturstofftage Hertweck, Christian Irsee, Germany

Kick off Meeting FunComPath: From colonization to infection: dissection of the commensal-to-pathogen shift of Candida albicans Hube, Bernhard Jena, Germany


SCIENTIFIC AWARDSPREISE UND AUSZEICHNUNGEN

2014

Brakhage, Axel A. Main Award of the German Society for Hygene and Microbiology Deutsche Gesellschaft für Hygiene und Mikrobiologie

Bretschneider, Tom Young Scientists‘ Award Leibniz Association

Bretschneider, Tom Science Award of the Beutenberg Campus e.V. Beutenberg-Campus Jena e.V.

Bretschneider, Tom DECHEMA PhD Award for Natural Product Research DECHEMA Gesellschaft für Chemische Technik und Biotechnologie e.V.

Bretschneider, Tom Junior Scientists‘ Award Protein Analytics Arbeitstagung Mikromethoden in der Pro-teinchemie

Chen, Qian Chinese Government Award for Outstanding Self-Financed Students Abroad Chinese Government

Chen, Qian ICS Trainee Award International Complement Society

Cyrulies, Michael medac Research Award medac GmbH, Wedel

Hillmann, Falk Junior Scientists‘ Award of the German- speaking Mycological Society Deutschsprachige Mykologische Ge-sellschaft

Hillmann, Falk Poster Award 12th European Conference on Fungal Genetics

Hoffmann, Kerstin medac Research Award medac GmbH, Wedel

Horn, Fabian medac Research Award medac GmbH, Wedel

Hube, Bernhard Honorary Member of the German-speaking Mycological Society Deutschsprachigen Mykologischen Ge-sellschaft

Hube, Bernhard Main Award of the German Society for Hygiene and Microbiology Deutsche Gesellschaft für Hygiene und Mikrobiologie

Ishida, Keishi medac Research Award medac GmbH, Wedel

Kämmer, Philipp Presentation Award 4th International Student Conference on Microbial Communication

Kloß, Florian Leibniz Drug of the Year Leibniz Forschungsverbund Wirkstoffe und Biotechnologie

Kroll, Kristin Presentation Award 7. ILRS Symposium

Linde, Jörg medac Research Award medac GmbH, Wedel

Linden, Justus Presentation Award 7. ILRS Symposium

Mattern, Derek Hybrid Award ESF-EMBO Conference on Synthetic Biology of Antibiotic Production II

Meinel, Christian Poster Award 4th International Student Conference on Microbial Communication

Micklisch, Sven Presentation Award ProRetina Meeting PRO RETINA-Stiftung zur Verhütung von Blindheit

Pidot, Sacha medac Research Award medac GmbH, Wedel

Schwartze, Volker medac Research Award medac GmbH, Wedel

Shelest, Ekaterina medac Research Award medac GmbH, Wedel

Skerka, Christine Galenus von Pergamon Award for Funda-mental Research Springer Medizin Verlag GmbH

Valiante, Vito medac Research Award medac GmbH, Wedel

Zipfel, Peter F. Galenus von Pergamon Award for Funda-mental Research Springer Medizin Verlag GmbH

2015

Brakhage, Axel Honorary Member of the German-speaking Mycological Society Deutschsprachige Mykologische Ge-sellschaft

Brandes, Susanne Presentation Award 8. ILRS Symposium

Brunke, Sascha medac Research Award medac GmbH, Wedel

154

Brunke, Sascha Publication Award of the German-speaking Mycological Society Deutschsprachige Mykologische Gesellschaft

Buhlmann, Denise Poster Award European Meeting on Complement in Hu-man Disease

Buhlmann, Denise Presentation Award 8. ILRS Symposium

Chen, Qian Dissertation Award of the Biological and Pharmaceutical Faculty Friedrich-Schiller-Universität Jena

Chen, Qian Rainer Greger Dissertation Award Deutsche Gesellschaft für Nephrologie

Chen, Qian Science Award of the Beutenberg Campus e.V. Beutenberg-Campus Jena e.V.

Dahse, Hans-Martin medac Research Award medac GmbH, Wedel

Geib, Elena Poster Award Fungal Genetics Conference

Heine, Daniel medac Research Award medac GmbH, Wedel

Hertweck, Christian Member of the Deutsche Akademie der Naturforscher Leopoldina

Hertweck, Christian Gottfried Wilhelm Leibniz Prize Deutsche Forschungsgemeinschaft

Hertweck, Christian Gottlieb Memorial Award University of Illinois

Hertweck, Christian Wilhelm Manchot Research Professorship Technische Universität München

Hortschansky, Peter medac Research Award medac GmbH, Wedel

Ishida, Keishi medac Research Award medac GmbH, Wedel

Jacobsen, Ilse Scientific Award of the German-speaking Mycological Society Deutschsprachige Mykologische Ge-sellschaft

Kloß, Florian Dissertation Award of the Faculty of Chemis-try and Geosciences Friedrich Schiller-Universität Jena

Lin, Yuchen Young Researcher Award International Symposiums on AMD

Linden, Justus Poster Award 8. ILRS Symposium

Meinel, Christian Poster Award 5th International Student Conference on Microbial Communication

Meinel, Christian Presentation Award European Meeting on Complement in Hu-man Disease

Meinel, Christian Presentation Award 5th International Student Conference on Microbial Communication

Meyer, Florian medac Research Award medac GmbH, Wedel

Nett, Markus DECHEMA Poster Award DECHEMA Gesellschaft für Chemische Technik und Biotechnologie e.V.

Novohradskà, Silvia Poster Award 5th International Student Conference on Microbial Communication

Pidot, Sacha medac Research Award medac GmbH, Wedel

Roth, Martin medac Research Award medac GmbH, Wedel

Schmidt, Hella Best Poster Communication Award Annual Scientific Meeting of the European Society for Clinical Investigation

Schmidt, Hella Poster Award Wissenschaftliche Tagung der Deutschsprachigen Mykologischen Ge-sellschaft

Schreiner, Maria medac Research Award medac GmbH, Wedel

Seccareccia, Ivana Presentation Award 5th International Student Conference on Microbial Communication

Seider, Katja Publication Award of the German-speaking Mycological Society Deutschsprachige Mykologische Ge-sellschaft

Shabuer, Gulimila medac Research Award medac GmbH, Wedel

Sundaram, Srividhya Poster Award 8. ILRS Symposium

Sundaram, Srividhya Poster Award VAAM International Workshops

Üzüm, Zerrin Poster Award 5th International Student Conference on microbial communication

Wartenberg, Anja Scientific Award of the special group „Eukaryotic Pathogens“ of the German Society for Hygene and Microbiology Deutsche Gesellschaft für Hygiene und Mikrobiologie

Wartenberg, Anja medac Research Award medac GmbH, Wedel


CALLS FOR APPOINTMENTS RUFE

Jacobsen, Ilse Call for a W3 professorship in microbial immunology at Friedrich Schiller University Jena (2014) Ruf auf eine W3-Professur für Mikrobielle Immunologie an die Friedrich-Schiller-Uni-versität Jena (2014)

Skerka, Christine Call for an Adjunct Professor of Immuno-regulation at the Friedrich Schiller Uni- versity Jena (2014) Ruf auf eine apl. Professur für Immunregu-lation an die Friedrich-Schiller-Universität Jena (2014)

Brock, Matthias Call for an Assistant Professor, Fungal Biology Group, University of Nottingham (2015) Ruf als Assistant Professor, Fungal Biology Group, University of Nottingham (2015)

Nett, Markus Call for a W2 professorship in Technical Biology at the Technical University of Dortmund (2015) Ruf auf eine W2-Professur für Technische Biologie an die Technische Universität Dortmund (2015)

156

GRADUATIONS PROMOTIONEN

2014

Amin, Shayista In vitro, in vivo and in ovo interactions of human pathogenic fungus Aspergillus fumigatus Friedrich-Schiller-Universität Jena

Böcker, Selina Funktionelle Charakterisierung der Interakti-on zwischen Typ-III-sekretierten Protein IncB aus Chlamydia psittaci und dem humanen Protein Snapin Friedrich-Schiller-Universität Jena

Chen, Qian The role of complement in autoimmune disease Friedrich-Schiller-Universität Jena

Hummert, Christian Analyse und Interpretation der Varianz von Genexpressionsdaten Friedrich-Schiller-Universität Jena

Keller, Sophia Interaktion der humanpathogenen Mikro- organismen Aspergillus fumigatus und Pseu-domonas aeruginosa Friedrich-Schiller-Universität Jena

Kloss, Florian Totalsynthese, Struktur-Aktivitäts-Beziehun-gen und Funktionen von Closthioamid, dem ersten Antibiotikum aus einem anaeroben Bakterium Friedrich-Schiller-Universität Jena

Kopka, Isabell Komplementaktivität im proximalen Tubulus der Niere - Implikationen bei Nierener- krankungen und der Abwehr von Mikro- organismen Friedrich-Schiller-Universität Jena

Kreutzer, Martin Isolation, structure elucidation and charac-terization of bacterial siderophores Friedrich-Schiller-Universität Jena

Kroll, Kristin Mechanisms of hypoxic adaptation in Asper-gillus fumigatus Friedrich-Schiller-Universität Jena

Lapp, Katrin Die Rolle von reaktiven Stickstoffspezies in der Interaktion von Aspergillus fumigatus mit humanen neutrophilen Granulozyten Friedrich-Schiller-Universität Jena

Letzel, Anne-Catrin Genome Mining von anaeroben Bakterien zur Entdeckung von Wirkstoffen Friedrich-Schiller-Universität Jena

Lüdecke, Claudia Investigation of bacterial cell adhesion mechanisms on nanorough biomaterials surfaces using a novel in vitro testing device Friedrich-Schiller-Universität Jena

Macheleidt, Juliane Proteinkinase A-regulierte Biosynthese eines neuen, immunsupprimierenden Naturstoffs durch den humanpathogenen Pilz Aspergillus fumigatus Friedrich-Schiller-Universität Jena

Micklisch, Sven Funktionelle Charakterisierung von Age-rela-ted maculopathy susceptibility 2 – ARMS2 Friedrich-Schiller-Universität Jena

Möbius, Nadine Molekulare Untersuchungen zu Symbiose-faktoren und Toxin-Biosynthese in Burkholde-ria-Rhizopus-Interaktionen Friedrich-Schiller-Universität Jena

Mohan, Sarbani Complement Escape Mechanisms of Strep-tococcus pneumoniae Friedrich-Schiller-Universität Jena

Otzen, Christian Untersuchungen zum Fettsäure- und Propi-onatmetabolismus in Candida albicans Friedrich-Schiller-Universität Jena

Tuppatsch, Katja Assoziierte Proteine und regulatorische Funktionen des CCAAT-Bindekomplexes in Aspergillus nidulans Friedrich-Schiller-Universität Jena

Ueberschaar, Nico Mutasynthese und Charakterisierung von Antitumoralen Wirkstoffen aus Streptomy-ceten Friedrich-Schiller-Universität Jena

Vlaic, Sebastian Integrated knowledge-assisted ge-nome-wide transcriptome data analysis of the non-alcoholic fatty liver disease Friedrich-Schiller-Universität Jena

Wartenberg, Anja In vitro- und in vivo- Mikroevolutionsstudien zum Anpassungsvermögen von Candida albicans an wirtsspezifische Umgebungen Friedrich-Schiller-Universität Jena

Zang, Emerson Droplet-based microfluidic screening for novel antibiotics from Actinobacteria Friedrich-Schiller-Universität Jena


2015

Altwasser, Robert Gene regulatory network inference in human pathogenic fungi Friedrich-Schiller-Universität Jena

Arnold, Heike Generierung und Charakterisierung spezi-fischer VHH-Antikörperformate gegen den humanen Immunrezeptor CTLA-4 Friedrich-Schiller-Universität Jena

Baldin, Clara Tor dependent regulatory circuits and regula-tion of melanin biosynthesis in Aspergillus fumigatus Friedrich-Schiller-Universität Jena

Biermann, Michael Rare amino acid related physiological stress response in recombinant Escherichia coli fermentations Friedrich-Schiller-Universität Jena

Chankhamjon, Pranatchareeya Chemical and biochemical analysis of myco-toxin biosynthesis in Aspergillus Species Friedrich-Schiller-Universität Jena

Essig, Fabian Analyse der Aktivierung des angeborenen Immunsystems durch Candida spp. mittels Lebendzellmikroskopie Friedrich-Schiller-Universität Jena

Fatangare, Amol Elucidating 2-deoxy-2-fluoro-D-glucose translocation, metabolism, and application in plants Friedrich-Schiller-Universität Jena

Franke, Jakob Genome mining-based identification and study of natural products from the human pathogenic Burkholderia mallei group Friedrich-Schiller-Universität Jena

Funk, Jana Biochemische Charakterisierung und Lokali-sierung des Enolase-Allergens humanpatho-gener Pilze Friedrich-Schiller-Universität Jena

Gebser, Björn Osmoregulation of microalgae and release of climate relevant gases Friedrich-Schiller-Universität Jena

Gressler, Markus Produktion und Identifikation phyto- und zy-totoxischer Metabolite des opportunistisch humanpathogenen Pilzes Aspergillus terreus Friedrich-Schiller-Universität Jena

Kästner, Julia Identifizierung von immunreaktiven Protei-nen in Chlamydia psittaci-infizierten Rindern Friedrich-Schiller-Universität Jena

König, Claudia Aktivierung des stillen Fumicyclin-Clusters in Aspergillus fumigatus durch mikrobielle Kommunikation mit Streptomyces rapamy-cinicus Friedrich-Schiller-Universität Jena

Leonhardt, Ines Impact of the fungal quorum sensing mole-cule farnesol on human innate immune cells Friedrich-Schiller-Universität Jena

Manchanda, Himanshu A systems biology approach – quantification and molecular insights into influenza-A virus infection Friedrich-Schiller-Universität Jena

Mokhtari, Zeinab Quantitative analysis of interacting and migrating immune cells from image data Friedrich-Schiller-Universität Jena

Pähtz, Vera Mechanismen der Wirtsadaptation von Aspergillus fumigatus Friedrich-Schiller-Universität Jena

Roß, Claudia Toxinbiosynthese von Burkholderia spp. in Interaktionen mit Pilzen, Pflanzen und Insekten Friedrich-Schiller-Universität Jena

Schieferdecker, Sebastian Secondary metabolites from predatory bacteria – isolation, structure elucidation and bioactivity Friedrich-Schiller-Universität Jena

Senftleben, Ulrike CFHR5 bindet Oberflächen über seine Mittelregion und erlaubt neue Einblicke in die Pathogenese der C3G Friedrich-Schiller-Universität Jena

Sugimoto, Yuki Genetic engineering and functional analyses of the aureothin and neoaureothin biosyn-thetic pathways Friedrich-Schiller-Universität Jena

Walther, Elisabeth Hemmung der Neuraminidase von Strep-tococcus pneumoniae im Synergismus mit Influenza-A-Viren Friedrich-Schiller-Universität Jena

158

BACHELOR / MASTER / DIPLOMA THESESBACHELOR- / MASTER- / DIPLOMARBEITEN

2014

BACHELOR

Beudert, Matthias Bildung von Phenazin-Konjugaten mit biogenen Thiolen Friedrich-Schiller-Universität Jena

Beyer, Clemens Untersuchungen zur antimikrobiellen Wirkung von Extrakten aus Himbeere (Rubus idaeus L.) und Frauenmantel (Alchemilla L.) auf Escherichia coli und S. enterica ssp. enterica ser. typhimurium in Verbindung mit unterschiedlichen, für die Veterinärmedizin Ernst-Abbe-Hochschule Jena

Brumhard, Philipp Die Bedeutung Morphologie-assozi-ierter Gene von Candida albicans für die Pathogenese im intraperitonealen Infektionsmodell und die Interaktion mit Immunzellen Friedrich-Schiller-Universität Jena

Globig, Philipp Charakterisierung einer HUS (Hämoly-tisch-Urämisches-Syndrom) assozierten Mutation in CFHR2 Friedrich-Schiller-Universität Jena

Hille, Fabrice Konstruktion und Charakterisierung von Deletionsmutanten Eisenmetabolismus- assoziierter Gene in Candida glabrata Friedrich-Schiller-Universität Jena

Lehmann, Tobias Identifizierung und Isolierung bakterieller Se-kundärmetabolite mit amöbizidaler Wirkung Ernst-Abbe-Hochschule Jena

Mathe, Laura Entwicklung von stressinduzierbaren Reporterkassetten in E. coli Ernst-Abbe-Hochschule Jena

Melzer, Katharina Interaktion von Lichtheimia corymbifera mit murinen Alveolar-Makrophagen Friedrich-Schiller-Universität Jena/ Ernst-Abbe-Hochschule Jena

Nessel, Diana Interaktion von Candida albicans mit Hepato-zyten: Identifizierung potentiell immunpatho-logischer Gene Friedrich-Schiller-UniversitätJena

Niederleithinger, Marie Untersuchung der genetischen Grundlage der Caryoynencin-Biosynthese in Burkholde-ria caryophylli Friedrich-Schiller-Universität Jena

Reinelt, Daniela Funktionsstudien zu Apolipoprotein E (ApoE) im angeborenen Immunsystem Friedrich-Schiller-Universität Jena

Sitte, Elisabeth Isolierung und Strukturaufklärung von Sekundärmetaboliten aus insektenassoziier-ten Burkholderien Friedich-Schiller-Universität Jena

Sperlein, Stefanie Inaktivierung von Biosynthesegenen in Cupriavidus basilensis Friedrich-Schiller-Universität Jena

Sprenger, Marcel Zelluläre Funktion und Rolle von Candida albicans EED1 in Quorum Sensing Friedrich-Schiller-Universität Jena

Trottmann, Felix Untersuchung zur Wirkung von Signalmole-külen auf das Metabolom von Burkholderia thailandensis Friedrich-Schiller-Univesität Jena

Wolf, Antonia Anreicherung chlamydialer Partikel und RNA Isolation zur Vorbereitung einer simultanen Pathogen/Wirt Transkriptomanalyse Friedrich-Schiller-Universität Jena

MASTER

Balzer, Philipp Heterologe Expression putativer NRPS/PKS-Hybrid Gencluster aus Clostridium species in Bacillus subtilis Friedrich-Schiller-Universität Jena

Behr, Sarah Identifizierung und initiale Charakterisierung humaner Wirtsproteine als Interaktions-partner immunogener oder sekretierter chlamydialer Proteine Friedrich-Schiller-Universität Jena

Conrad, Theresia Bioinformatic pathway analysis of gene ex-pression and secretome response of human lung epithelia cells induced via toll-like, TNF and IFNgamma receptors Friedrich-Schiller-Universität Jena

Dietrich, Stefanie Automated image analysis of picolitre droplets in a microfluidic system Friedrich-Schiller-Universität Jena

Dworschak, Jan Chemoenzymatische Synthese von Disul-fid-überprückten Diketopiperazinen Friedrich-Schiller-Universität Jena

Frühauf, Andre Candida albicans glycerol-3-phosphate dehy-drogenase 2 (Gpd2) is a terminal comple-ment pathway inhibitor Friedrich-Schiller-Universität Jena

Geib, Elena Sporulationsinduzierte Metabolite in Apergil-lus terreus Friedrich-Schiller-Universität Jena

Heim, Lisanne Funktionelle Untersuchung zur Interaktion von IncA aus Chlamydia trachomatis mit dem Wirtszellprotein G3BP1 Friedrich-Schiller-Universität Jena

Hermenau, Ron Metabolic profliling of plant-associated and soil-derived Burkholderia specias for new antibiotics Friedrich-Schiller-Universität Jena

Hörhold, Franziska Age-related alternative splicing – a multiple species approach Friedrich-Schiller-Universität Jena


Korp, Juliane Untersuchungen zu der Endiin-Biosynthese in Actinomyceten Friedrich-Schiller-Universität Jena

Kreisel, Christian Fungal gene enrichment analysis: Develop-ment of fungiFun2 Friedrich-Schiller-Universität Jena

Kurth, Colette Purification and characterisation of a non-ri-bosomal peptide synthetase from Agrobacte-rium tumefaciens C58 Friedrich-Schiller-Universität Jena

Mitter, Anna Lisa Four dimensional molecular imaging of insulin-induced bone deformities in chick embryos by PET/CT Friedrich-Schiller-Universität Jena

Schneider, Martin Preparation of high purity RNA from elemen-tary and reticulate bodies of Chlamydophila psittaci for differential sequencing analysis Friedrich-Schiller-Universität Jena

Sieber, Patricia Age-related dual data analysis of miR-NA-Seq and mRNA-Seq data from the JenAge project Friedrich-Schiller-Universität Jena

Spielberg, Steffi Transcriptional profiling of farnesol-mediat-ed dendritic cell maturation Friedrich-Schiller-Universität Jena

Sprenger, Marcel Zelluläre Funktion und Rolle von Candida albicans EED1 in Quorum Sensing Friedrich-Schiller-Universität Jena

Witteck, Lisa Generierung und Charakterisierung von Varianten eines kameliden VHH-Antikörpers zur Detektion von Amyloidfibrillen Friedrich-Schiller-Universität Jena

2015

BACHELOR

Baischew, Asat Naturstoffe aus Streptomyces sp. ACT97, einem Antagonisten des Mycoparasiten Sepedonium chrysospermum Friedrich-Schiller-Universität Jena

Bauer, Ruth Interrogation of a non-canonical branching domain of the Rhizoxin polyketide synthase Friedrich-Schiller-Universität Jena

Büttner, Hannah Charakterisierung der primären und sekun-dären Hefen der Candida albicans eed1Δ Mutante in vitro Friedrich-Schiller-Universität Jena

Fiedler, Julia Characterization of a Candida albicans mnn9 mutant in its interaction with epithelial cells Friedrich-Schiller-Universität Jena

Hanke, Wiebke Biochemische Charakterisierung einer nichtribosomalen Peptidsynthetase aus dem räuberischen Bakterium Herpetosiphon aurantiacus Friedrich-Schiller-Universität Jena

Jagusch, Hans Heterologe Produktion und Charakterisie-rung von flavin-abhängigen Halogenasen aus Armillaria mellea Friedrich-Schiller-Universität Jena

Juraschitz, Marc Charakterisierung der Rolle spezifischer Candida albicans Gene in der Interaktion mit intestinalen Epithelzellen Friedrich-Schiller-Universität Jena

Kirschmann, Carolyn Lois Analysis of ECE1 deletion mutants and Ece1-derived peptides of the human fungal pathogen Candida albicans Friedrich-Schiller-Universität Jena

Mikolajczyk, Rebecca Einfluss von Hypoxie auf das Schädigungs- und Invasionspotential von C. albicans auf Enterozyten Friedrich-Schiller-Universität Jena

Morgner, Bianca Analyse eines tRNA-modifizierenden Enzy-ms unter virulenzassoziierten Bedingungen in Candida albicans Friedrich-Schiller-Universität Jena

Rappe, Marcus Charakterisierung der pilzlichen Enzyme Tryptophandecarboxylase und α-Aminoa-dipatreduktase aus Ceriporiopsis subvermi-spora Brandenburgische Technische Universität Cottbus-Senftenberg

Schröter, Madita C3 convertase and C3b autoantibodies in C3 glomerulopathy Friedrich-Schiller-Universität Jena

MASTER

Alene, Medhanie G. The consequences of complement inhibition on the human innate immune response to Candida albicans Friedrich-Schiller-Universität Jena

Athanasopoulou, Kalliopi Mining the genomes of Variovorax boroni-cumulans and Serratia symbiotica for novel metallophores Friedrich-Schiller-Universität Jena

Bauer, Laura Comparative analysis of immune response patterns to sepsis-causing pathogens using a human whole blood infection model Friedrich-Schiller-Universität Jena

Blickensdorf, Marco Agent based modeling of cell migration and shape analysis Friedrich-Schiller-Universität Jena

160

Böhm, Matthias Die Peptidsynthetase NPS8 aus Serpula lacrymans S7: Bestimmung der Substratspe-zifität der Adenylierungsdomäne Friedrich-Schiller-Universität Jena

Bratovanov, Evgeni Potential role of siderophores in the sym-biosis Rhizopus microsporus – Burkholderia rhizoxinica Friedrich-Schiller-Universität Jena

Desouky, Ahmed Genome mining-guided search for new nat-ural products from the predatory bacterium Cupriavidus basilensis OR16 Friedrich-Schiller-Universität Jena

Franke, Annika The impact of the Candida albicans protein Ece1 on macrophage damage and inflam-matory response Friedrich-Schiller-Universität Jena

Halder, Luke D. Characterization of the immediate early response of human blood monocyte cells to human pathogenic fungi Candida albicans Friedrich-Schiller-Universität Jena

Haueisen, Jana Charakterisierung von drei Arginin-Methyl- transferasen von Aspergillus fumigatus Friedrich-Schiller-Universität Jena

Hilliger, Michael Comparative fluorescence-microscopic in-vestigations of the phagocytosis of virulent and avirulent strains of the human-patho-genic Zygomycetes genus Lichtheimia by murine macrophages Friedrich-Schiller-Universität Jena

Hübler, Ron Random forest classification of circulating tumor cells from microscopy images Friedrich-Schiller-Universität Jena

Klapper, Martin The role of secondary metabolites in Dictyo- stelium disocideum – Bacteria interactions Friedrich-Schiller-Universität Jena

Lauer, Alexa The role of Ece1 in Candida albicans iron acquisition from erythrocytes and TR146 oral epithelial cells Friedrich-Schiller-Universität Jena

Lauterbach, Tom Biosynthetische Studien zum neuartigen Naturstoff Rhizochelin aus Agrobacterium tumefaciens C58 Friedrich-Schiller-Universität Jena

Muslihudeen, Abdul Aziz Microbial diversity in giant tiger shrimp (Pe-naeus monodon) mutant of great economic potential Friedrich-Schiller-Universität Jena

Oetama, Vincensius Comparative analysis of the fecal microbi-ome of Penaeus monodon from Jakarta Bay and Bali Friedrich-Schiller-Universität Jena

Pöllath, Christine Identifizierung und Charakterisierung Chlamydosporen-assoziierter Gene in Candi-da dubliniensis und Candida albicans Friedrich-Schiller-Universität Jena

Prätzsch, Dominique Purification of infectious and non-infectious Chlamydia psittaci particles and enrichment of primary transcripts for differential RNA sequencing Friedrich-Schiller-Universität Jena

Reiher, Nadine Charakterisierung der Candida albicans Pro-tease Pra1 (pH- regulated antigen 1) Friedrich-Schiller-Universität Jena

Rudnick, Ramona Die Rolle von Komplementregulatoren in der C3-Glomerulopathie Friedrich-Schiller-Universität Jena

Runtze, Anna Untersuchungen zur Interaktion von Asper-gillus fumigatus mit alveolaren Makrophagen Friedrich-Schiller-Universität Jena

Tank, Cedric Entwicklung eines Stress-basierten Repor-tersystems in Escherichia coli zur Detektion antimikrobieller Substanzen Ernst-Abbe-Hochschule Jena

Totzauer, Sören Implementation of molecular diffusion by the matrix exponential approach in an agent-based framework Friedrich-Schiller-Universität Jena

Zöllkau, Markus Steigerung der Produktausbeute durch Optimierung der Proteinbiosynthese und Aufreinigung von Fab-Fragmenten in Escheri-chia coli Ernst-Abbe-Hochschule Jena

Zubiria Barrera, Cristina The role of N-glycosylation and environ-mental alkalinization in Candida glabrata cell biology and macrophage interaction Friedrich-Schiller-Universität Jena

IMPRINT

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Phone: +49 3641 532-1000Mail: [email protected]

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Editorial BoardProf. Dr. Axel A. BrakhageDr. Michael RammDr. Christine VoglerMonika Weiß

Design and LayoutBernd Adam

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RESEARCH REPORT 2014 | 2015 · erforscht die Kommunikation zwischen Bakteri-en und Eukaryoten....

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