On the relevance of Aspergillus fumigatus sexuality for virulence and secondary metabolism of this human pathogenic mould.
Final Report Abstract
Opportunistic infections caused by human pathogenic fungi pose a significant threat for distinct groups of patients. Immunosuppressed individuals or those who have received a stem cell transplant are at high risk to suffer from an invasive fungal infection, due to the fact that we are constantly confronted with spores of such environmental pathogens. Infections by the omnipresent mould Aspergillus fumigatus are of special relevance as, given their significant rates of mortality, they may be lethal for the respective patient. Virulence of this filamentous fungus is supported by various traits, among them its pronounced stress resistance, metabolic versatility, and also immunological characteristics. While the asexual phase in the life cycle of this saprophyte has been studied extensively for decades, the sexual phase with fruiting body development and generation of recombinant meispores has been characterized insufficiently, especially in the context of virulence or resistance. On the genetic level, the sexual cycle of A. fumigatus is regulated via a bipolar mating-type system. There, the two transcription factors MAT-1-1 and MAT1-2-1 act as central regulators that are expressed in an exclusive manner from an idiomorphic region located on chromosome III. Overall aim of the funded research project was to comprehensively survey the transcriptomes driven by MAT1-1-1 and MAT1-2-1, accompanied by the functional characterisation of selected components. Based on RNAseq data that had been generated from isolates expressing the MAT1-encoded regulators in a conditional manner, various insight were gained. For instance, a significant influence of the matingtype regulators on secondary metabolism became evident. This was demonstrated for several different natural products produced by A. fumigatus and scrutinized further for the biosynthesis of fumagillin and pseurotin and correspondingly the encoding supercluster. Furthermore, function of a MAT1-2-associated gene was studied and the role of tomA, a gene that is transcribed in strict dependency of the mating-type master regulators. By in-depth analysis of the MAT1-specific transcriptomes, existence of the so far unknown sexual pheromone, the a-factor-like peptide encoded by the ppgB gene, could be demonstrated. Further investigations covered the extensive phenotyping of ascospores, as they had been generated by crossing experiments, with an emphasis on stress resistance and virulence in established experimental models. These studies, however, did not reveal significant differences compared to conidia, the asexual spores that serve as infectious particles. In essence, the research project as it has been supported by the DFG allowed a thorough and continuative investigation of the matingtype system of a relevant opportunistic fungal pathogen. Gained insights and conclusions close knowledge gaps about a neglected and understudied phase in the life cycle of A. fumigatus and give perspective for a better understanding of associated determinants for virulence and resistance.
Publications
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CRISPR-Cas9, the new kid on the block of fungal molecular biology. Medical Mycology, 55(1), 16-23.
Krappmann, Sven
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The novel Aspergillus fumigatus MAT1-2-4 mating-type gene is required for mating and cleistothecia formation. Fungal Genetics and Biology, 108(2017, 11), 1-12.
Yu, Yidong; Amich, Jorge; Will, Cornelia; Eagle, Carly E.; Dyer, Paul S. & Krappmann, Sven
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Mating‐type factor‐specific regulation of the fumagillin/pseurotin secondary metabolite supercluster in Aspergillus fumigatus. Molecular Microbiology, 110(6), 1045-1065.
Yu, Yidong; Blachowicz, Adriana; Will, Cornelia; Szewczyk, Edyta; Glenn, Steven; Gensberger‐Reigl, Sabrina; Nowrousian, Minou; Wang, Clay C. C. & Krappmann, Sven
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The master regulator MAT1-1-1 of fungal mating binds to its targets via a conserved motif in the human pathogen Aspergillus fumigatus. G3, 11(2).
Ramšak, Barbara; Markau, Jessica; Pazen, Tobias; Dahlmann, Tim A; Krappmann, Sven & Kück, Ulrich
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The infectious propagules of Aspergillus fumigatus are coated with antimicrobial peptides. Cellular Microbiology, 23(3).
Dümig, Michaela; Binder, Jasmin; Gaculenko, Anastasia; Daul, Franziska; Winandy, Lex; Hasenberg, Mike; Gunzer, Matthias; Fischer, Reinhard; Künzler, Markus & Krappmann, Sven
