Gliotoxin, a Known Virulence Factor in the Major Human Pathogen Aspergillus fumigatus, Is Also Biosynthesized by Its Nonpathogenic Relative .

is a major opportunistic human pathogen. Multiple traits contribute to pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate virulence. The genome of , a very close nonpathogenic relative of , contains a biosynthetic gene cluster that is homologous to the gliotoxin cluster. However, is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen and the nonpathogen , we examined whether strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of We found that biosynthesizes gliotoxin under the same conditions as However, whereas loss of , a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce virulence, we found that loss (and loss of secondary metabolite production) in does not influence its virulence. These results suggest that LaeA-regulated secondary metabolites are virulence factors in the genomic and phenotypic background of the major pathogen but are much less important in the background of the nonpathogen Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic species will require detailed characterization of their biological, chemical, and genomic similarities and differences. is a major opportunistic fungal pathogen of humans, but most of its close relatives are nonpathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether , a nonpathogenic close relative of , can produce gliotoxin, a mycotoxin known to contribute to virulence. We discovered that the nonpathogenic produces gliotoxin under the same conditions as those of the major pathogen However, we also discovered that, in contrast to what has previously been observed in , the loss of secondary metabolite production in does not alter its virulence. Our results are consistent with the "cards of virulence" model of opportunistic fungal disease, in which the ability to cause disease stems from the combination ("hand") of virulence factors ("cards") but not from individual factors .