Calcineurin is required for virulence of Cryptococcos neoformans

Audrey Odom, Scott Muir, Eric Lim, Dena L. Toffaletti, John Perfect, Joseph Heitman

Research output: Contribution to journalArticle

359 Scopus citations

Abstract

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°C but not at 24°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°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.

Original languageEnglish
Pages (from-to)2576-2589
Number of pages14
JournalEMBO Journal
Volume16
Issue number10
DOIs
StatePublished - May 15 1997

Keywords

  • Calcineurin
  • Cryptococcus neoformans
  • Cyclosporin A
  • FK506
  • Virulence

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    Odom, A., Muir, S., Lim, E., Toffaletti, D. L., Perfect, J., & Heitman, J. (1997). Calcineurin is required for virulence of Cryptococcos neoformans. EMBO Journal, 16(10), 2576-2589. https://doi.org/10.1093/emboj/16.10.2576