Calcineurin Is Essential for Virulence in Candida albicans

Abstract

Calcineurin is a conserved Ca2؉ -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 ⌬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 ⌬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.

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…62,71,72 These in vitro results are supported by gene deletion studies showing that calcineurin-defective C. albicans mutants were more sensitive to stress conditions than isogenic wild-type controls, were markedly hypersensitive to azoles, and had attenuated virulence in mice with systemic candidiasis. [73][74][75] Although that hypovirulence is attributed to sensitivity of C. albicans to killing by serum mediated by Ca 2+ , no reported data have indicated that pharmacological inhibition of calcineurin also protects against calcium stress. Interestingly, loss of function crz1 C. albicans mutants, defective in crz1 which encoded a downstream transcription effector of the calcineurin, Crz1, were not sensitive to serum and exhibited no decrease in virulence.…”

The putative flavin carrier family FlcA-C is important forAspergillus fumigatusvirulence

“…15 The signaling by calcium is very important for fungal virulence and drug resistance. 1,2 Calcineurin has been demonstrated to be required for virulence in human fungal pathogens, such as Cryptococcus spp, Candida spp, Paracoccidioides brasiliensis, and Aspergillus fumigatus; [16][17][18][19][20][21][22][23] and fungal plant pathogens, such as Sclerotinia scleotiorum, Botrytis cinerea, Magnaporthe oryza, and Ustilago spp. [24][25][26][27][28] In all these fungal pathogens, calcineurin is important for growth, morphology, state transitions, cation homeostasis, stress responses, and cell membrane and cell wall integrity pathways.…”

Comparative genomics of MAP kinase and calcium–calcineurin signalling components in plant and human pathogenic fungi

“…All these components showed a high degree of sequence identity (40-90%) among the fungal species studied. In the human pathogens C. albicans, C. neoformans and A. fumigatus, calcineurin was required for survival in serum and for virulence (Bader et al, 2003;Blankenship et al, 2003;Da Silva Ferreira et al, 2007;Fox et al, 2001;Odom et al, 1997;Steinbach et al, 2006Steinbach et al, , 2007. In the plant pathogen Sclerotinia sclerotiorum, the calcineurin orthologue controls sclerotial development and infection (Harel et al, 2006).…”