Genetic Analysis of Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance.
is an emerging fungal pathogen and a serious global health threat as the majority of clinical isolates display elevated resistance to currently available antifungal drugs. Despite the increased prevalence of infections, the mechanisms governing drug resistance remain largely elusive. In diverse fungi, the evolution of drug resistance is enabled by the essential molecular chaperone Hsp90, which stabilizes key regulators of cellular responses to drug-induced stress. Hsp90 also orchestrates temperature-dependent morphogenesis in , a key virulence trait. However, the role of Hsp90 in the pathobiology of remains unknown. In order to study regulatory functions of Hsp90 in , we placed under the control of a doxycycline-repressible promoter to enable transcriptional repression. We found that Hsp90 is essential for growth in and that it enables tolerance of clinical isolates with respect to the azoles, which inhibit biosynthesis of the membrane sterol ergosterol. High-level azole resistance was independent of Hsp90 but dependent on the ABC transporter , deletion of which resulted in abrogated resistance. Strikingly, we discovered that undergoes a morphogenetic transition from yeast to filamentous growth in response to depletion or cell cycle arrest but not in response to other cues that induce filamentation. Finally, we observed that this developmental transition is associated with global transcriptional changes, including the induction of cell wall-related genes. Overall, this report provides a novel insight into mechanisms of drug tolerance and resistance in and describes a developmental transition in response to perturbation of a core regulator of protein homeostasis. Fungal pathogens pose a serious threat to public health. is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, , which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in and uncovers a distinct developmental program regulated by Hsp90.
|Year of Publication||
2019 01 29
|PubMed Central ID||
U19 AI110818 / AI / NIAID NIH HHS / United States
MOP-86452 / CIHR / Canada
MOP-119520 / CIHR / Canada
FDN-154288 / CIHR / Canada