Calcineurin Controls Hyphal Growth, Virulence, and Drug Tolerance of Candida tropicalis

ABSTRACTCandida tropicalis, a species closely related toCandida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. LikeC. albicansandCandida dubliniensis,C. tropicalisis able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear inC. tropicalis. Recently, echinocandin- and azole-resistantC. tropicalisisolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of theC. tropicalisgenes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis inC. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions inC. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance inC. tropicalis.