Evidence for the role of calcineurin in morphogenesis and calcium homeostasis during mycelium-to-yeast dimorphism of Paracoccidioides brasiliensis


Autoria(s): Campos, Claudia B. L.; Di Benedette, Joao Paulo T.; Morais, Flavia V.; Ovalle, Rafael; Nobrega, Marina P.
Contribuinte(s)

Universidade Estadual Paulista (UNESP)

Data(s)

27/05/2014

27/05/2014

01/10/2008

Resumo

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°C to 37°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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Formato

1856-1864

Identificador

http://dx.doi.org/10.1128/EC.00110-08

Eukaryotic Cell, v. 7, n. 10, p. 1856-1864, 2008.

1535-9778

http://hdl.handle.net/11449/70595

10.1128/EC.00110-08

2-s2.0-54249101880

2-s2.0-54249101880.pdf

Idioma(s)

eng

Relação

Eukaryotic Cell

Direitos

closedAccess

Palavras-Chave #calcineurin #calcium #cyclosporin #enzyme inhibitor #fungal protein #tacrolimus #drug effect #enzymology #gene expression regulation #genetics #growth, development and aging #homeostasis #human #metabolism #microbiology #morphogenesis #mycelium #Paracoccidioides #South American blastomycosis #temperature #Calcineurin #Calcium #Cyclosporine #Enzyme Inhibitors #Fungal Proteins #Gene Expression Regulation, Fungal #Homeostasis #Humans #Morphogenesis #Mycelium #Paracoccidioidomycosis #Tacrolimus #Temperature #Fungi #Paracoccidioides brasiliensis
Tipo

info:eu-repo/semantics/article