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Eukaryotic Cell, October 2008, p. 1856-1864, Vol. 7, No. 10
1535-9778/08/$08.00+0     doi:10.1128/EC.00110-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Evidence for the Role of Calcineurin in Morphogenesis and Calcium Homeostasis during Mycelium-to-Yeast Dimorphism of Paracoccidioides brasiliensis{triangledown}

Claudia B. L. Campos,1* Joao Paulo T. Di Benedette,1 Flavia V. Morais,1 Rafael Ovalle,2 and Marina P. Nobrega1,{dagger}

Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba (UNIVAP), Sao Jose dos Campos, Sao Paulo, 12244-000, Brazil,1 Department of Biology, Brooklyn College of the City University of New York, New York 112102

Received 27 March 2008/ Accepted 21 August 2008

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 Ca2+ levels increased in hyphae immediately after temperature-induced dimorphism. The chelation of Ca2+ with extracellular (EGTA) or intracellular (BAPTA) calcium chelators inhibited temperature-induced dimorphism, whereas the addition of extracellular Ca2+ 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 Ca2+ homeostasis and decreased mRNA transcription of the CCH1 gene for the plasma membrane Ca2+ 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 Ca2+/calmodulin-dependent phosphatase calcineurin controls hyphal and yeast morphology, M-Y dimorphism, growth, and Ca2+ 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.

* Corresponding author. Mailing address: Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba (UNIVAP), Av. Shishima Hifumi, 2911, Urbanova, Sao Jose dos Campos, Sao Paulo, 12244-000, Brazil. Phone and fax: (55) 12 3947-1119. E-mail: cbcampos{at}univap.br

{triangledown} Published ahead of print on 5 September 2008.

{dagger} Present address: Dept. of Biociencias e Diagnostico Bucal, UNESP, Sao Jose dos Campos, Sao Paulo, Brazil.

Eukaryotic Cell, October 2008, p. 1856-1864, Vol. 7, No. 10
1535-9778/08/$08.00+0     doi:10.1128/EC.00110-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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