Characterizing the pathogenic, genomic, and chemical traits of Aspergillus fischeri, a close relative of the major human fungal pathogen Aspergillus fumigatus

<i>Aspergillus fischeri </i>is a close evolutionary relative of the major cause of invasive mold infections, <i>Aspergillus fumigatus</i>. In contrast to <i>A. fumigatus</i>, <i>A. fischeri </i>rarely causes invasive disease even though it is commonly found in diverse environments, including hospitals. Thus, it remains unclear why <i>A. fischeri </i>causes less human disease. To begin addressing this question, we characterized the pathogenic, genomic, and secondary metabolic similarities and differences between <i>A. fischeri </i>and <i>A. fumigatus</i>. We observed multiple differences between the two species for phenotypes related to pathogenesis, including that <i>A. fischeri </i>is less virulent than <i>A. fumigatus </i>in multiple murine models of invasive disease, exhibits slower growth in low oxygen environments, and is more sensitive to oxidative stress. In contrast, the genomic similarity between the two species is high; ~90% of the <i>A. fumigatus </i>proteome is conserved in <i>A. fischeri</i>, including 48 / 49 genes known to be involved in <i>A. fumigatus </i>virulence. However, only 10 / 33 <i>A. fumigatus </i>biosynthetic gene clusters (BGCs) likely involved in the production of secondary metabolites are conserved in <i>A. fischeri </i>and only 13 / 48 <i>A. fischeri </i>BGCs are conserved in <i>A. fumigatus</i>. Detailed chemical characterization of <i>A. fischeri </i>cultures grown on multiple substrates identified multiple secondary metabolites, including two new compounds and one never before isolated as a natural product. Interestingly, an <i>A. fischeri </i>deletion mutant of <i>laeA</i>, 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 between the two species. These results suggest that the non-pathogenic <i>A. fischeri </i>possesses many of the genes important for <i>A. fumigatus </i>pathogenicity but is divergent with respect to its ability to thrive under host-relevant conditions and its secondary metabolism. <br>