title: Calcineurin is essential for Candida albicans survival in serum and virulence.
abstract: Calcineurin is a calcium-activated protein phosphatase that is the target of the immunosuppressants cyclosporin A and FK506. In T cells, calcineurin controls nuclear import of the NF-AT transcription factor and gene activation. In plants and fungi, calcineurin functions in stress responses (e.g., temperature, cations, and pH) and is necessary for the virulence of the fungal pathogen Cryptococcus neoformans. Here we show that calcineurin is also required for the virulence of another major fungus that is pathogenic to humans, Candida albicans. C. albicans calcineurin mutants had significantly reduced virulence in a murine model of systemic infection. In contrast to its role in C. neoformans, calcineurin was not required for C. albicans survival at 37 degrees C. Moreover, C. albicans calcineurin mutant strains exhibited no defects in known Candida virulence traits associated with host invasion, including filamentous growth, germ tube formation, and adherence to and injury of mammalian cells. C. albicans calcineurin mutant strains failed to colonize and grow in the kidneys of infected animals and were unable to survive when exposed to serum in vitro. Our studies illustrate that calcineurin has evolved to control aspects of the virulence of two divergent fungal pathogens via distinct mechanisms that can be targeted to achieve broad-spectrum antifungal action.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Blankenship
authors.forename: Floyd L
authors.initials: FL
authors.lastname: Wormley
authors.forename: Molly K
authors.initials: MK
authors.lastname: Boyce
authors.forename: Wiley A
authors.initials: WA
authors.lastname: Schell
authors.forename: Scott G
authors.initials: SG
authors.lastname: Filler
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
mesh_terms: D000818:Animals; D001769:Blood / Q000382:microbiology*; D019703:Calcineurin / Q000502:physiology*; D002176:Candida albicans / Q000166:cytology / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D009061:Mouth Mucosa / Q000166:cytology; D009154:Mutation; D013696:Temperature; D014471:Umbilical Veins / Q000166:cytology; D014774:Virulence
chemical_list: D019703:Calcineurin