Calcineurin signaling: lessons from Candida species

Human fungal infections have significantly increased in recent years due to the emergence of immunocompromised patients with AIDS and cancer. Among them, Candida species are frequently isolated and associated with high mortality if not appropriately treated. Current antifungal drugs (azoles, echinocandins and polyenes) are not sufficient to combat Candida species particularly those that are drug resistant. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is an attractive antifungal drug target, and its inhibitor (FK506 or cyclosporin A) can be combined with azoles or echinocandins for use against multidrug-resistant Candida species. The role of calcineurin in the hyphal growth of Candida albicans is controversial, but its roles in C. dubliniensis, C. tropicalis and C. lusitaniae can be demonstrated. In addition, calcineurin is required for virulence of Candida species in murine systemic, ocular or urinary infection models. However, the requirement for calcineurin substrate Crz1 in these infection models varies in Candida species, suggesting that Crz1 has diverse functions in different Candida species. Besides being critical for growth in serum of Candida species, calcineurin is critical for plasma membrane integrity and growth at body temperature (37°C) uniquely in C. glabrata, suggesting that Candida calcineurin controls pathogenesis via various novel mechanisms. In this review, we summarize studies of calcineurin signaling and hyphal growth, virulence and its relationship with drug tolerance in Candida species, focusing on the divergent and conserved functions.