Aneuploidy promotes transient stress adaptation and metabolic flexibility in the human fungal pathogen Aspergillus fumigatus.

Aneuploidy enables adaptive responses that facilitate stress resistance and persistence under changing conditions in eukaryotes ranging from yeasts and fungi to human cancer cells. Aspergillus fumigatus is a soil-resident mold and the most prevalent etiologic agent of invasive fungal infections globally. Invasive aspergillosis has an alarmingly high mortality rate, and fungal persistence in the infection microenvironment often renders treatments unsuccessful. Treatment failures can result from innate or acquired antifungal drug resistance and from fungal adaptation to other stresses encountered during infection, including nutrient limitation, immune cell activity, and changes in pH and oxygen tension. Survival in ecological and host environments therefore necessitates an ability to dynamically adapt to stress. We find that exposure of A. fumigatus to the calcineurin inhibitor FK506 selects for unstable whole-chromosome duplications that alleviate the polarized growth defects caused by calcineurin inhibition. The neosartoricin biosynthetic gene cluster (nsc BGC) is transcriptionally induced in chromosome 7 (chr7) aneuploids exposed to FK506, and constitutive genetic induction of this cluster is sufficient to largely recapitulate in a haploid background the response to FK506 in the aneuploid state. We further show that aneuploids undergo extensive metabolic rewiring but do not produce detectable neosartoricin, thus revealing global and cross-pathway effects resulting from the aneuploid state and from activation of the transcriptional regulator-encoding gene nscR. Aneuploid chromosome duplications also reduce susceptibility to the clinical antifungal voriconazole, which underscores the utility of aneuploidy as a flexible adaptive strategy. These findings offer new insights into how unstable aneuploidy transiently alters stress responses and metabolism in a major human pathogen.