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Cited by 186Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence

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Blankenship, Jill R., Wormley, Floyd L., Boyce, Molly K., Schell, Wiley A., Filler, Scott G., Perfect, John R., Heitman, Joseph·2003·Eukaryotic Cell
DOI 10.1128/ec.2.3.422-430.2003PMC PMC161442
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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°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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  • The C. glabrata Δcnb1 strain phenotype (increased susceptibility to azoles and cell wall-damaging agents, decreased virulence) is consistent with previous findings for other pathogenic fungi.

    “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 <i>Candida glabrata</i> (2010) · cites this paper as [4]

  • Calcineurin is essential for C. albicans survival in serum and virulence in a murine model of infection.

    “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

  • Calcineurin is a conserved nonessential protein phosphatase critical for morphogenesis, drug resistance, and virulence in multiple Candida species.

    “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 <i>Cryptococcus neoformans</i> highlights key roles in stress tolerance and virulence (2022) · cites this paper as Blankenship et al. 2003

  • In contrast to C. neoformans, calcineurin is dispensable for survival of C. albicans at 37 or 42°C, and C. albicans cnb1 mutant strains had no defects in germination and filamentous growth.

    “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

  • The C. albicans cnb1 mutant showed filamentous growth in vivo but 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.

    “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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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
ORCID
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
DOI
10.1128/ec.2.3.422-430.2003
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
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
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 › Epidemiology › 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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