Susceptibility to caspofungin is regulated by temperature and is dependent on calcineurin in Candida albicans

Abstract

ABSTRACT Candida albican s is a prevalent opportunistic human fungal pathogen. Echinocandins are first-line drugs for the treatment of invasive candidiasis. Molecular mechanisms of resistance to echinocandins have been extensively studied; however, the effect of physiological factors on antifungal efficacy of echinocandins is unexplored. Here, we found temperature-modulated susceptibility to caspofungin in medium-independent and strain background-independent manner in C. albicans . Deletions of protein kinase C (PKC) pathway and calcineurin-Crz1 signaling pathway genes conferred hypersensitivity to caspofungin, but only deletion or pharmacological inhibition of calcineurin subunits inverted the temperature effect on susceptibility to caspofungin. Furthermore, the enhanced growth at lower temperature was not due to altered expression of some established genes such as FKS , CHS , or CHT genes; PKC or calcineurin pathway genes; or HSP90 . The expressions of other heat shock protein genes, including HSP12 and HSP70 , were higher at lower temperature. We posit that the temperature-modulated susceptibility to caspofungin is a non-canonical mechanism that is dependent on heat shock proteins and calcineurin. IMPORTANCE Echinocandins are the newest antifungal drugs and are first-line treatment option for life-threatening systemic infections. Due to lack of consensus regarding what temperature should be used when evaluating susceptibility of yeasts to echinocandins, typically either 30°C, 35°C, or 37°C is used. However, the impact of temperature on antifungal efficacy of echinocandins is unexplored. In the current study, we demonstrated that Candida albicans laboratory strain SC5314 was more susceptible to caspofungin at 37°C than at 30°C. We also found that calcineurin was required for temperature-modulated caspofungin susceptibility. Surprisingly, the altered caspofungin susceptibility was not due to differential expression of some canonical genes such as FKS , CHS , or CHT genes. The molecular mechanism of temperature-modulated caspofungin susceptibility is undetermined and deserves further investigations.