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Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence
Open accessAbstract
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°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.
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“For example, the observed C. glabrata Δcnb1 strain phenotype, which is characterized by an increased susceptibility to azoles and cell wall-damaging agents as well as decreased virulence, is consistent with previous findings for other pathogenic fungi, such as C. albicans (2-4, 27), C. neoformans (11, 18, 21), and A. fumigatus (9, 30).”
From Roles of Calcineurin and Crz1 in Antifungal Susceptibility and Virulence of Candida glabrata (2010) · cites this paper as [4]
In the citing paper
“Calcineurin has been shown to be essential for C. albicans survival in serum and virulence in a murine model of infection, but the molecular mechanisms involved are still unknown (Blankenship et al. 2003;Bader et al. 2003;Sanglard et al. 2003).”
From Functional characterization of the Candida albicans CRZ1 gene encoding a calcineurin-regulated transcription factor (2005) · cites this paper as Blankenship et al. 2003
In the citing paper
“Calcineurin is a conserved nonessential protein phosphatase critical for morphogenesis, drug resistance, and virulence in multiple Candida species (Cruz et al. 2002; Blankenship et al. 2003; Chen et al. 2011, 2012, 2014; Zhang et al. 2012).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Blankenship et al. 2003
In the citing paper
“In contrast to C. neoformans, calcineurin was dispensable for survival of C. albicans at 37 or 42° C, and the C. albicans cnb1 mutant strains had no defects in germination and filamentous growth (Blankenship et al., 2003).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Blankenship et al., 2003
In the citing paper
“Although the C. albicans cnb1 mutant strain showed filamentous growth in vivo, it failed to grow in a mouse model of disseminated candidiasis and was unable to survive in serum, revealing evolutionarily distinct control aspects of calcineurin over virulence of two divergent fungal pathogens via distinct mechanisms (Blankenship and Heitman, 2005; Blankenship et al., 2003; Kraus et al., 2003).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Blankenship et al., 2003
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Self-citation
Metadata
- Authors
- Blankenship, J. R., Wormley, F. L., Boyce, M. K., Schell, W. A., Filler, S. G., Perfect, J. R., & Heitman, J.
- Affiliations
- Departments of Molecular Genetics and Microbiology
- Medicine
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Heitman, Joseph
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2003-06
- Volume
- 2
- Issue
- 3
- Pages
- 422-430
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC161442
- OpenAlex
- W2171788590
- Cited by
- 186
- References
- 65
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 2 · 2017: 9 · 2016: 12 · 2015: 8 · 2014: 13 · 2013: 8 · 2012: 9
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (RR00425)
- U.S. Public Health Service (R01 PA-98-100)
- National Institute of Allergy and Infectious Diseases (P01-AI44975, T32AI07392, P01AI044975, R01AI028388, R01 AI28388, R01 AI50438, AI-44975, R01AI050438, T32AI007392)
- National Center for Research Resources (M01RR000425, M01-RR00425)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- calcineurin, Candida albicans, fungal virulence, systemic candidiasis, serum survival, Cryptococcus neoformans, filamentous growth, germ tube formation, host cell adhesion, kidney colonization, antifungal drug targets
- MeSH terms
- Animals, Blood, Candida albicans, Cells, Cultured, Humans, Kidney, Mice, Inbred BALB C, Mouth Mucosa, Mutation, Temperature, Umbilical Veins, Virulence, Calcineurin, Endothelial Cells, Mice
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