Calcineurin Is Essential for Virulence in Candida albicans

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Abstract
Calcineurin is a conserved Ca 2+ -calmodulin-activated, serine/threonine-specific protein phosphatase that regulates a variety of physiological processes, e.g., cell cycle progression, polarized growth, and adaptation to salt and alkaline pH stresses. In the pathogenic yeast Cryptococcus neoformans , calcineurin is also essential for growth at 37°C and virulence. To investigate whether calcineurin plays a role in the virulence of Candida albicans , the major fungal pathogen of humans, we constructed C. albicans mutants in which both alleles of the CMP1 gene, encoding the calcineurin catalytic subunit, were deleted. The C. albicans Δ cmp1 mutants displayed hypersensitivity to elevated Na + , Li + , and Mn 2+ concentrations and to alkaline pH, phenotypes that have been described after calcineurin inactivation in the related yeast Saccharomyces cerevisiae . Unlike S. cerevisiae calcineurin mutants, which exhibit reduced susceptibility to high Ca 2+ concentrations, growth of C. albicans was inhibited in the presence of 300 mM CaCl 2 after the deletion of CMP1 , demonstrating that there are also differences in calcineurin-mediated cellular responses between these two yeast species. In contrast to C. neoformans , inactivation of calcineurin did not cause temperature sensitivity in C. albicans . In addition, hyphal growth, an important virulence attribute of C. albicans , was not impaired in the Δ cmp1 mutants under a variety of inducing conditions. Nevertheless, the virulence of the mutants was strongly attenuated in a mouse model of systemic candidiasis, demonstrating that calcineurin signaling is essential for virulence in C. albicans .