@article {Mead430728, author = {Matthew E. Mead and Sonja L. Knowles and Huzefa A. Raja and Sarah R. Beattie and Caitlin H. Kowalski and Jacob L. Steenwyk and Lilian P. Silva and Jessica Chiaratto and Laure N.A. Ries and Gustavo H. Goldman and Robert A. Cramer and Nicholas H. Oberlies and Antonis Rokas}, title = {Characterizing the pathogenic, genomic, and chemical traits of Aspergillus fischeri, the closest sequenced relative of the major human fungal pathogen Aspergillus fumigatus}, elocation-id = {430728}, year = {2018}, doi = {10.1101/430728}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Aspergillus fischeri is a very close evolutionary relative of the major cause of invasive mold infections, Aspergillus fumigatus. In contrast to A. fumigatus, A. fischeri rarely causes invasive disease, but why such a discrepancy between the species exists is unknown. To begin to address 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. In contrast, ~90\% of the A. fumigatus proteome is conserved in A. fischeri, including all but one of the previously known A. fumigatus genetic determinants important for virulence. However, the two species differed substantially in their biosynthetic gene clusters (BGCs) that are likely involved in the production of secondary metabolites, with only 10 / 33 A. fumigatus BGCs also conserved in A. fischeri. 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, a deletion mutant in A. fischeri of the ortholog of a master regulator of secondary metabolism, laeA, 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 less-pathogenic A. fischeri possesses many of the genes important for A. fumigatus pathogenicity but is divergent with respect to its secondary metabolism and its ability to thrive under infection-relevant conditions.Importance Aspergillus fumigatus is the primary cause of aspergillosis, a multi-faceted and devastating disease associated with severe morbidity and mortality worldwide. A. fischeri is a very close relative of A. fumigatus, but it is rarely associated with human disease. To gain insights into the underlying causes of this remarkable difference in pathogenicity, we compared the two organisms for a range of infection-relevant biological and chemical characteristics. We found that disease progression in multiple A. fischeri mouse models was much slower and caused less mortality than A. fumigatus. The two species also exhibited different growth profiles when placed in a range of infection-relevant conditions, such as low oxygen. Interestingly, we also found that A. fischeri contains all but one of the genes previously identified as essential for A. fumigatus virulence. However, the two species differ significantly in their secondary metabolic pathways and profiles. The similarities and differences that we identified shed light into the evolutionary origin of a major fungal pathogen.}, URL = {https://www.biorxiv.org/content/early/2018/09/29/430728}, eprint = {https://www.biorxiv.org/content/early/2018/09/29/430728.full.pdf}, journal = {bioRxiv} }