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Calcineurin is required for virulence of Cryptococcus neoformans.

Identifieur interne : 001A91 ( Main/Exploration ); précédent : 001A90; suivant : 001A92

Calcineurin is required for virulence of Cryptococcus neoformans.

Auteurs : A. Odom [États-Unis] ; S. Muir ; E. Lim ; D L Toffaletti ; J. Perfect ; J. Heitman

Source :

RBID : pubmed:9184205

Descripteurs français

English descriptors

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 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.

DOI: 10.1093/emboj/16.10.2576
PubMed: 9184205
PubMed Central: PMC1169869


Affiliations:


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Le document en format XML

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<term>Calcineurin (MeSH)</term>
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<term>Cryptococcus neoformans (drug effects)</term>
<term>Cryptococcus neoformans (genetics)</term>
<term>Cryptococcus neoformans (pathogenicity)</term>
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<term>Temperature (MeSH)</term>
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<term>Antifongiques (pharmacologie)</term>
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<term>Ciclosporine (pharmacologie)</term>
<term>Cryptococcus neoformans (effets des médicaments et des substances chimiques)</term>
<term>Cryptococcus neoformans (génétique)</term>
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<term>Gènes fongiques (MeSH)</term>
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<term>Modèles génétiques (MeSH)</term>
<term>Mutagenèse (MeSH)</term>
<term>Phosphoprotein Phosphatases (génétique)</term>
<term>Polyènes (pharmacologie)</term>
<term>Protéines de liaison à la calmoduline (génétique)</term>
<term>Protéines fongiques (génétique)</term>
<term>Recombinaison génétique (MeSH)</term>
<term>Régulation de l'expression des gènes fongiques (MeSH)</term>
<term>Résistance microbienne aux médicaments (MeSH)</term>
<term>Similitude de séquences d'acides aminés (MeSH)</term>
<term>Sirolimus (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Séquence nucléotidique (MeSH)</term>
<term>Tacrolimus (pharmacologie)</term>
<term>Température (MeSH)</term>
<term>Virulence (génétique)</term>
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<term>Base Sequence</term>
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<div type="abstract" xml:lang="en">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.</div>
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<AbstractText>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.</AbstractText>
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