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

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