Deciphering the phenotypic and genomic traits that underlie the evolution of pathogenicity differences among Aspergillus fumigatus and its close relatives

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PROJECT SUMMARY Aspergillus fumigatus is a major human fungal pathogen that infects – often killing – hundreds of thousands each year. A few closely related species are also pathogenic but cause fewer infections. In contrast, most other closely related species are not pathogenic. Pathogens have originated repeatedly from non-pathogens, suggesting that the ability to cause disease or pathogenicity has evolved multiple times independently in this lineage. The observed spectrum of pathogenicity cannot be explained by differences in species' ecologies or by ascertainment bias, indicating that the repeated evolution of Aspergillus pathogenicity has, at least partially, a genetic basis. Several key traits – and their underlying genes and pathways – are known to be associated with A. fumigatus pathogenicity, including virulence, growth at the human body temperature, and the production of secondary metabolites. In contrast, we know surprisingly little about the repeated evolution of pathogenicity in Aspergillus and the variation in the traits and genetic elements that contributed to its origins. Whether pathogenic species share traits and genetic elements that are absent in non-pathogens (“conserved pathogenicity” model) or each pathogen contains a unique suite of traits and genetic elements that distinguish it from its non-pathogenic relatives (“species-specific pathogenicity” model) remains unknown; a third model, essentially a mix of the other two, is also possible, under which some traits and genetic elements that contribute to pathogenicity are conserved and some are species-specific. Elucidating which model explains the repeated evolution of Aspergillus pathogenicity is key for developing strategies to combat infections, identifying genetic elements that contribute to virulence, and predicting new pathogen emergence. This project will test these models and advance our understanding of the evolution of Aspergillus pathogenicity by investigating: the variation of species (and strains within species) that span the pathogenicity spectrum with respect to virulence, growth at the human body temperature, and secondary metabolite production (Aim 1); the genomic and transcriptomic variation associated with the observed differences in pathogenicity (Aim 2), and; how genetic elements that vary between pathogens and non-pathogens have contributed to the evolution of fungal pathogenicity (Aim 3). The project is innovative because: it will address fundamental, largely unanswered, questions in medical mycology, such as how fungal pathogenicity evolved and why A. fumigatus infects hundreds of thousands yearly but its very close relatives do not; b) it will generate invaluable resources, such as comprehensive, in-depth examinations of variation for key disease-relevant traits and genetic elements in a lineage of closely related fungi that vary extensively in their pathogenicity, and; it will lead to the generation of novel, genetically tractable model organisms for studying how major fungal pathogens originate from historically innocuous organisms.