Project A1

Cross-talk of Aspergillus fumigatus with neutrophilic granulocytes

Neutrophils are the most important effector cells in the immune response against Aspergillus fumigatus. In project A1, we aim at understanding the mechanisms how neutrophils control A. fumigatus infections.

In the first funding period we developed novel methods for the bioinformatics-based analysis of live cell imaging. This allowed automated quantification of phagocytosis and the identification of fungal molecules inhibiting phagocytosis. Furthermore, quantitative analysis of the dual proteome of A. fumigatus and neutrophils by LC-MS was established. This led to the discovery of novel human proteins involved in the interactions with this fungus.

In the second funding period our research will focus on the identification of novel effector mechanisms of neutrophils against A. fumigatus, building on our discoveries from the first funding period. We will also characterize immune cell receptors potentially involved in the cross-talk of neutrophils with A. fumigatus. For this, we will use immune cells from knockout mice, cell lines, monoclonal antibodies that block specific receptors and mouse infection models for invasive aspergillosis. Finally, we will analyze patient groups for single nucleotide polymorphisms (SNPs) in the proteins that interact with A. fumigatus as basis for translational approaches.

Summary of research to characterize the interaction of different A. fumigatus morphotypes with neutrophilic granulocytes
Summary of research to characterize the interaction of different A. fumigatus morphotypes with neutrophilic granulocytes
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@uni-jena.de

Publications
Author Year Title Journal Links
Schmidt H, Vlaic S, Krüger T, Schmidt F, Balkenhohl J, Dandekar T, Guthke R, Kniemeyer O, Heinekamp T, Brakhage AA 2018 Proteomics of Aspergillus fumigatus conidia-containing phagolysosomes identifies processes governing immune evasion. Mol Cell Proteomics mcp.RA117.000069 (Epub ahead of print) 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 Microbiol
Pohlers S, Martin R, Krüger T, Hellwig D, Hänel F, Kniemeyer O, Saluz HP, Van Dijck P, Ernst JF, Brakhage A, Mühlschlegel FA, Kurzai O 2017 Lipid Signaling via Pkh1/2 regulates fungal CO2 sensing through the kinase Sch9. mBio 8 pii: e02211-16 PubMed
Johns A, Scharf DH, Gsaller F, Schmidt H, Heinekamp T, Straßburger M, Oliver JD, Birch M, Beckmann N, Dobb KS, Gilsenan J, Rash B, Bignell E, Brakhage AA, Bromley MJ 2017 A nonredundant Phosphopantetheinyl transferase, PptA, is a novel antifungal target that directs secondary metabolite, Siderophore, and Lysine biosynthesis in Aspergillus fumigatus and is critical for pathogenicity. mBio 18: 8 pii: e01504-16 PubMed
de Vries RP, Riley R, Wiebenga A, Aguilar-Osorio G, Amillis S, Uchima CA, Anderluh G, Asadollahi M, Askin M, Barry K, Battaglia E, Bayram Ö, Benocci T, Braus-Stromeyer SA, Caldana C, Cánovas D, Cerqueira GC, Chen F, Chen W, Choi C, Clum A, Dos Santos RA, Damásio AR, Diallinas G, Emri T, Fekete E, Flipphi M, Freyberg S, Gallo A, Gournas C, Habgood R, Hainaut M, Harispe ML, Henrissat B, Hildén KS, Hope R, Hossain A, Karabika E, Karaffa L, Karányi Z, Kraševec N, Kuo A, Kusch H, LaButti K, Lagendijk EL, Lapidus A, Levasseur A, Lindquist E, Lipzen A, Logrieco AF, MacCabe A, Mäkelä MR, Malavazi I, Melin P, Meyer V, Mielnichuk N, Miskei M, Molnár ÁP, Mulé G, Ngan CY, Orejas M, Orosz E, Ouedraogo JP, Overkamp KM, Park HS, Perrone G, Piumi F, Punt PJ, Ram AF, Ramón A, Rauscher S, Record E, Riaño-Pachón DM, Robert V, Röhrig J, Ruller R, Salamov A, Salih NS, Samson RA, Sándor E, Sanguinetti M, Schütze T, Sepčić K, Shelest E, Sherlock G, Sophianopoulou V, Squina FM, Sun H, Susca A, Todd RB, Tsang A, Unkles SE, van de Wiele N, van Rossen-Uffink D, Oliveira JV, Vesth TC, Visser J, Yu JH, Zhou M, Andersen MR, Archer DB, Baker SE, Benoit I, Brakhage AA, Braus GH, Fischer R, Frisvad JC, Goldman GH, Houbraken J, Oakley B, Pócsi I, Scazzocchio C, Seiboth B, vanKuyk PA, Wortman J, Dyer PS, Grigoriev IV 2017 Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus. Genome Biol 18: 28 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
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
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 the bifunctional bHLH DevR and MADS-box RlmA 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, Kortgen A, Bauer M, Giamarellos-Bourboulis EJ, Dimopoulos G, Brakhage AA, Kniemeyer O 2016 Immunoproteomic analysis of antibody responses to extracellular proteins of Candida albicans revealing the importance of 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
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
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
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
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
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
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 PubMed
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
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
Scharf DH, Heinekamp T, Brakhage AA 2014 Human and plant fungal pathogens: the role of secondary metabolites. PLoS Pathog 10: e1003859 PLoS Pathog