| dc.description.abstract | Globally, severe fungal infections in humans cause serious disease and kill millions of people annually, but fungal infections remain understudied and poorly understood. The genus Aspergillus includes several hundred species of filamentous fungi, including major human pathogens like Aspergillus fumigatus and Aspergillus flavus. Aspergillus species are a leading cause of fungal disease, responsible for many serious human infections such as fungal keratitis and aspergillosis, but only a small fraction of species within Aspergillus have been implicated in human infections.
To identify unique factors leading to A. flavus pathogenicity, I began by combining bioinformatic techniques with traditional microbiological assays and other experimental methods to assess chemical diversity and virulence in A. flavus and close relatives, Aspergillus arachidicola, Aspergillus parasiticus, and Aspergillus nomiae. I found that each species had genomic and phenotypic strain level differences. Genomes of A. flavus strains included in the study varied in ~1.5% of genes, but the strains differed in their ability to kill Galleria mellonella, a model for fungal disease. All species and strains exhibited strain-level differences in secondary metabolites produced. I also found that A. flavus was able to infect eyes in a mouse model at comparable rates to the major human pathogen A. fumigatus. I also surveyed A. flavus and 20 other Flavi species, comparing nuclear and mitochondrial genomes. Codon usage bias distinguished nuclear and mitochondrial genes, and examination of codon usage bias indicated that the evolutionary forces shaping nuclear and mitochondrial genomes differ. Overall, the nuclear and mitochondrial phylogenies showed similar topology, with minor incongruences among closely related species.
Finally, I assessed genetic diversity within A. flavus using a dataset of isolates from environmental and clinical sources. I used sequencing data from public databases and newly sequenced clinical isolates to examine the pan-genome and population structure of A. flavus. The pan-genome was considered closed, with 43% of the pan-genome consisting of accessory genes. I identified five populations of A. flavus and observed that clinical isolates were abundant in a single lineage and shared population-specific genetic characteristics. Findings from my research will add to our knowledge of A. flavus, an important fungal pathogen of humans. | |
