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Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis.
Eukaryot Cell. 2008 Oct; 7(10):1856-64.EC

Abstract

Paracoccidioides brasiliensis is a dimorphic fungus that causes paracoccidioidomycosis, the most prevalent human deep mycosis in Latin America. The dimorphic transition from mycelium to yeast (M-Y) is triggered by a temperature shift from 25 degrees C to 37 degrees C and is critical for pathogenicity. Intracellular Ca(2+) levels increased in hyphae immediately after temperature-induced dimorphism. The chelation of Ca(2+) with extracellular (EGTA) or intracellular (BAPTA) calcium chelators inhibited temperature-induced dimorphism, whereas the addition of extracellular Ca(2+) accelerated dimorphism. The calcineurin inhibitor cyclosporine A (CsA), but not tacrolimus (FK506), effectively decreased cell growth, halted the M-Y transition that is associated with virulence, and caused aberrant growth morphologies for all forms of P. brasiliensis. The difference between CsA and FK506 was ascribed by the higher levels of cyclophilins contrasted to FKBPs, the intracellular drug targets required for calcineurin suppression. Chronic exposure to CsA abolished intracellular Ca(2+) homeostasis and decreased mRNA transcription of the CCH1 gene for the plasma membrane Ca(2+) channel in yeast-form cells. CsA had no detectable effect on multidrug resistance efflux pumps, while the effect of FK506 on rhodamine excretion was not correlated with the transition to yeast form. In this study, we present evidence that Ca(2+)/calmodulin-dependent phosphatase calcineurin controls hyphal and yeast morphology, M-Y dimorphism, growth, and Ca(2+) homeostasis in P. brasiliensis and that CsA is an effective chemical block for thermodimorphism in this organism. The effects of calcineurin inhibitors on P. brasiliensis reinforce the therapeutic potential of these drugs in a combinatory approach with antifungal drugs to treat endemic paracoccidioidomycosis.

Authors+Show Affiliations

Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Urbanova, Sao Paulo, Brazil. cbcampos@univap.brNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18776037

Citation

Campos, Claudia B L., et al. "Evidence for the Role of Calcineurin in Morphogenesis and Calcium Homeostasis During Mycelium-to-yeast Dimorphism of Paracoccidioides Brasiliensis." Eukaryotic Cell, vol. 7, no. 10, 2008, pp. 1856-64.
Campos CB, Di Benedette JP, Morais FV, et al. Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis. Eukaryot Cell. 2008;7(10):1856-64.
Campos, C. B., Di Benedette, J. P., Morais, F. V., Ovalle, R., & Nobrega, M. P. (2008). Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis. Eukaryotic Cell, 7(10), 1856-64. https://doi.org/10.1128/EC.00110-08
Campos CB, et al. Evidence for the Role of Calcineurin in Morphogenesis and Calcium Homeostasis During Mycelium-to-yeast Dimorphism of Paracoccidioides Brasiliensis. Eukaryot Cell. 2008;7(10):1856-64. PubMed PMID: 18776037.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis. AU - Campos,Claudia B L, AU - Di Benedette,Joao Paulo T, AU - Morais,Flavia V, AU - Ovalle,Rafael, AU - Nobrega,Marina P, Y1 - 2008/09/05/ PY - 2008/9/9/pubmed PY - 2008/11/13/medline PY - 2008/9/9/entrez SP - 1856 EP - 64 JF - Eukaryotic cell JO - Eukaryot Cell VL - 7 IS - 10 N2 - Paracoccidioides brasiliensis is a dimorphic fungus that causes paracoccidioidomycosis, the most prevalent human deep mycosis in Latin America. The dimorphic transition from mycelium to yeast (M-Y) is triggered by a temperature shift from 25 degrees C to 37 degrees C and is critical for pathogenicity. Intracellular Ca(2+) levels increased in hyphae immediately after temperature-induced dimorphism. The chelation of Ca(2+) with extracellular (EGTA) or intracellular (BAPTA) calcium chelators inhibited temperature-induced dimorphism, whereas the addition of extracellular Ca(2+) accelerated dimorphism. The calcineurin inhibitor cyclosporine A (CsA), but not tacrolimus (FK506), effectively decreased cell growth, halted the M-Y transition that is associated with virulence, and caused aberrant growth morphologies for all forms of P. brasiliensis. The difference between CsA and FK506 was ascribed by the higher levels of cyclophilins contrasted to FKBPs, the intracellular drug targets required for calcineurin suppression. Chronic exposure to CsA abolished intracellular Ca(2+) homeostasis and decreased mRNA transcription of the CCH1 gene for the plasma membrane Ca(2+) channel in yeast-form cells. CsA had no detectable effect on multidrug resistance efflux pumps, while the effect of FK506 on rhodamine excretion was not correlated with the transition to yeast form. In this study, we present evidence that Ca(2+)/calmodulin-dependent phosphatase calcineurin controls hyphal and yeast morphology, M-Y dimorphism, growth, and Ca(2+) homeostasis in P. brasiliensis and that CsA is an effective chemical block for thermodimorphism in this organism. The effects of calcineurin inhibitors on P. brasiliensis reinforce the therapeutic potential of these drugs in a combinatory approach with antifungal drugs to treat endemic paracoccidioidomycosis. SN - 1535-9786 UR - https://www.unboundmedicine.com/medline/citation/18776037/Evidence_for_the_role_of_calcineurin_in_morphogenesis_and_calcium_homeostasis_during_mycelium_to_yeast_dimorphism_of_Paracoccidioides_brasiliensis_ L2 - http://ec.asm.org/cgi/pmidlookup?view=long&pmid=18776037 DB - PRIME DP - Unbound Medicine ER -