Characterizing the Pathogenic, Genomic, and Chemical Traits of , a Close Relative of the Major Human Fungal Pathogen .

is closely related to , the major cause of invasive mold infections. Even though is commonly found in diverse environments, including hospitals, it rarely causes invasive disease. Why causes less human disease than is unclear. A comparison of and for pathogenic, genomic, and secondary metabolic traits revealed multiple differences in pathogenesis-related phenotypes. We observed that NRRL 181 is less virulent than strain CEA10 in multiple animal models of disease, grows slower in low-oxygen environments, and is more sensitive to oxidative stress. Strikingly, the observed differences for some traits are of the same order of magnitude as those previously reported between strains. In contrast, similar to what has previously been reported, the two species exhibit high genomic similarity; ∼90% of the proteome is conserved in , including 48/49 genes known to be involved in virulence. However, only 10/33 biosynthetic gene clusters (BGCs) likely involved in secondary metabolite production are conserved in and only 13/48 BGCs are conserved in Detailed chemical characterization of cultures grown on multiple substrates identified multiple secondary metabolites, including two new compounds and one never before isolated as a natural product. Additionally, an deletion mutant of , a master regulator of secondary metabolism, produced fewer secondary metabolites and in lower quantities, suggesting that regulation of secondary metabolism is at least partially conserved. These results suggest that the nonpathogenic possesses many of the genes important for pathogenicity but is divergent with respect to its ability to thrive under host-relevant conditions and its secondary metabolism. is the primary cause of aspergillosis, a devastating ensemble of diseases associated with severe morbidity and mortality worldwide. is a close relative of but is not generally observed to cause human disease. To gain insights into the underlying causes of this remarkable difference in pathogenicity, we compared two representative strains (one from each species) for a range of pathogenesis-relevant biological and chemical characteristics. We found that disease progression in multiple mouse models was slower and caused less mortality than Remarkably, the observed differences between and strains examined here closely resembled those previously described for two commonly studied strains, AF293 and CEA10. and exhibited different growth profiles when placed in a range of stress-inducing conditions encountered during infection, such as low levels of oxygen and the presence of chemicals that induce the production of reactive oxygen species. We also found that the vast majority of genes known to be involved in virulence are conserved in , whereas the two species differ significantly in their secondary metabolic pathways. These similarities and differences that we report here are the first step toward understanding the evolutionary origin of a major fungal pathogen.