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Calcineurin is required for virulence of Cryptococcus neoformans.

Publication ,  Journal Article
Odom, A; Muir, S; Lim, E; Toffaletti, DL; Perfect, J; Heitman, J
Published in: EMBO J
May 15, 1997

Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhibit the Ca2+-regulated protein phosphatase calcineurin. We find that growth of the opportunistic fungal pathogen Cryptococcus neoformans is sensitive to CsA and FK506 at 37 degrees C but not at 24 degrees C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature. Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37 degrees C. The gene encoding the C. neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. Calcineurin mutant strains are viable but do not survive in vitro conditions that mimic the host environment (elevated temperature, 5% CO2 or alkaline pH) and are no longer pathogenic in an animal model of cryptococcal meningitis. Introduction of the wild-type calcineurin A gene complemented these growth defects and restored virulence. Our findings demonstrate that calcineurin is required for C. neoformans virulence and may define signal transduction elements required for fungal pathogenesis that could be targets for therapeutic intervention.

Duke Scholars

Published In

EMBO J

DOI

ISSN

0261-4189

Publication Date

May 15, 1997

Volume

16

Issue

10

Start / End Page

2576 / 2589

Location

England

Related Subject Headings

  • Virulence
  • Temperature
  • Tacrolimus
  • Sirolimus
  • Sequence Homology, Amino Acid
  • Recombination, Genetic
  • Rabbits
  • Polyenes
  • Phosphoprotein Phosphatases
  • Mutagenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Odom, A., Muir, S., Lim, E., Toffaletti, D. L., Perfect, J., & Heitman, J. (1997). Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J, 16(10), 2576–2589. https://doi.org/10.1093/emboj/16.10.2576
Odom, A., S. Muir, E. Lim, D. L. Toffaletti, J. Perfect, and J. Heitman. “Calcineurin is required for virulence of Cryptococcus neoformans.EMBO J 16, no. 10 (May 15, 1997): 2576–89. https://doi.org/10.1093/emboj/16.10.2576.
Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997 May 15;16(10):2576–89.
Odom, A., et al. “Calcineurin is required for virulence of Cryptococcus neoformans.EMBO J, vol. 16, no. 10, May 1997, pp. 2576–89. Pubmed, doi:10.1093/emboj/16.10.2576.
Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997 May 15;16(10):2576–2589.

Published In

EMBO J

DOI

ISSN

0261-4189

Publication Date

May 15, 1997

Volume

16

Issue

10

Start / End Page

2576 / 2589

Location

England

Related Subject Headings

  • Virulence
  • Temperature
  • Tacrolimus
  • Sirolimus
  • Sequence Homology, Amino Acid
  • Recombination, Genetic
  • Rabbits
  • Polyenes
  • Phosphoprotein Phosphatases
  • Mutagenesis