Project A1

Project Description

Aspergillus fumigatus is the most important air-borne human pathogenic fungus. It is estimated that every human inhales hundreds of spores (conidia) per day. Neutrophilic granulocytes are essential immune effector cells for preventing the infection by A. fumigatus. Neutrophils phagocytose resting and swollen conidia as well as germlings. They kill hyphae by adherence to their surface, as hyphae are too large to be engulfed. Until today, it is unclear by which mechanisms neutrophils control A. fumigatus. Furthermore, there is strong evidence that A. fumigatus modulates the activity of immune effector cells. A better understanding of the complex interaction between A. fumigatus and neutrophils is essential to elucidate the pathobiology of this important fungal pathogen and to develop novel strategies for therapeutic intervention.

In this project, we will investigate the interaction at three levels. (i) We will carry out a comprehensive proteome analysis, including secreted proteins. This information will be added to ongoing transcriptome analyses (RNA seq) and help identify the elements and regulatory circuits in both neutrophils and A. fumigatus characteristic for this interaction. They also form the basis of modelling. Identified genes will be functionally analysed (deletion mutants, overexpression, gfp fusions, mouse infection model) for their contribution to the infection and defence against neutrophils. The focus will be on genes with so far unknown functions. (ii) We will further elucidate the induction (and regulation) of Neutrophil Extracellular Traps (NETs) by A. fumigatus and identify components involved in this process of both the pathogen, by generating mutant strains, and the neutrophils. (iii) Comprehensive imaging of neutrophils interacting with the wild type and mutant strains of A. fumigatus affected in, e.g., biosynthesis of secondary metabolites, detoxification of host-derived reactive oxygen species, will be performed to define different stages of interaction and identify elements / areas of the pathogen important for recognition and also induction of NETosis. These data will be used to further improve automation of imaging and will be analysed bioinformatically. They provide valuable information on the interaction between pathogen and neutrophils.

Principal Investigator

Prof. Dr. Axel Brakhage
Prof. Dr. Axel Brakhage

Institute of Microbiology
Friedrich Schiller University Jena

Department of Molecular and Applied Microbiology HKI
Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute  

axel.brakhage@leibniz-hki.de

Publications

Author Year Title Journal Links
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(1) pii: e01439-14 PubMed
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 Aspergillus fumigatus. Mol Microbiol 93: 539-53 PubMed
Horn F, Schroeckh V, Netzker T, Guthke R, Brakhage AA, Linde J 2014 Draft genome sequence of Streptomyces iranensis. Genome Announc 2(4) pii: e00616-14 PubMed
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 virulence. Front Microbiol 5: 469 PubMed
Schwartze VU, Santiago AL, Jacobsen ID, Voigt K 2014 The pathogenic potential of the Lichtheimia genus revisited: Lichtheimia brasiliensis is a novel, non-pathogenic species. Mycoses 57 Suppl 3: 128-31 PubMed
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 involvement of the tor kinase in iron regulation. Proteomics 15: 2230-43 PubMed
Heinekamp T, Schmidt H, Lapp K, Pähtz V, Shopova I, Köster-Eiserfunke N, Krüger T, Kniemeyer O, Brakhage AA 2014 Interference of Aspergillus fumigatus with the immune response. Semin Immunopathol 37: 141-52 PubMed
Kraibooj K, Schoeler H, Svensson CM, Brakhage AA, Figge MT 2015 Automated quantification of the phagocytosis of Aspergillus fumigatus conidia by a novel image analysis algorithm. Front Microbiol 6: 549 PubMed
Scharf DH, Heinekamp T, Brakhage AA 2014 Human and plant fungal pathogens: the role of secondary metabolites. PLoS Pathog 10: e1003859 PLoS Pathog

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 PubMed

Horn F, Linde J, Mattern DJ, Walther G, Guthke R, Brakhage AA, Valiante V

2015

Draft genome sequence of the fungus Penicillium brasilianum MG11.

Genome Announc 3(5) pii: e00724-15 PubMed
Kroll K, Shekhova E, Mattern DJ, Thywissen A, Jacobsen ID, Strassburger M, Heinekamp T, Shelest E, Brakhage AA, Kniemeyer O 2016 The hypoxia-induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus.

Mol Microbiol 101: 92-108

PubMed
Teutschbein J, Simon S, Lother J, Springer J, Hortschansky P, Morton CO, Löffler J, Einsele H, Conneally E, Rogers TR, Guthke R, Brakhage AA, Kniemeyer O 2016 Proteomic profiling of serological responses to Aspergillus fumigatus antigens in patients with invasive aspergillosis.

J Proteome Res 15: 1580-91

PubMed
Lin CJ, Sasse C, Valerius O, Irmer 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 Pathog 11: e1005205 PubMed
Mattern DJ, Schoeler H, Weber J, Novohradská S, Kraibooj K, Dahse HM, Hillmann F, Valiante V, Figge MT, Brakhage AA 2015 Identification of the antiphagocytic trypacidin gene cluster in the human-pathogenic fungus Aspergillus fumigatus. Appl Microbiol Biotechnol 99: 10151-61 PubMed

Horn F, Linde J, Mattern DJ, Walther G, Guthke R, Scherlach K, Martin K, Brakhage AA, Petzke L, Valiante V

2016 Draft genome sequences of fungus Aspergillus calidoustus. Genome Announc 4(2): e00102-16 PubMed
Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A 2016 Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167: 1067-78.e16 PubMed
Krüger T, Luo T, Schmidt H, Shopova I, Kniemeyer O 2015 Challenges and strategies for proteome analysis of the interaction of human pathogenic fungi with host immune cells. Proteomes 3: 467-95 Proteomes
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: 141-52 PubMed
Valiante V, Baldin C, Hortschansky P, Jain R, Thywißen A, Straßburger M, Heinekamp T, Brakhage AA 2016 The Aspergillus fumigatus conidial melanin production is regulated by bifunctional MADS-box (RlmA) and bHLH (DevR) transcription factors. Mol Microbiol 102: 321-335. PubMed
Pollmächer J, Timme S, Schuster S, Brakhage AA, Zipfel PF, Figge MT 2016 Deciphering the counterplay of Aspergillus fumigatus infection and host inflammation by evolutionary games on graphs.

Sci Rep 6: 27807

PubMed
Luo T, Krüger T, Knüpfer U, Kasper L, Wielsch N, Hube B, Giamarellos-Bourboulis EJ, Kortgen A, Bauer M, Brakhage AA, Kniemeyer O 2016 Immune proteomic analysis of antibody responses to extracellular proteins of Candida albicans revealing the importance of protein glycosylation for antigen recognition. J Proteome Res 15: 2394-406 PubMed
Kniemeyer O, Ebel F, Krüger T, Bacher P, Scheffold A, Luo T, Strassburger M, Brakhage AA 2016 Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies. Proteomics Clin Appl 10: 910-21 PubMed
Bergfeld A, Dasari P, Werner S, Hughes TR, Song WC, Hortschansky P, Brakhage AA, Hünig T, Zipfel PF, Beyersdorf N 2017 Direct binding of the pH-regulated protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4+ T cells.

Front Microbiol 8: 844

Front Microbil