Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis

Ying-Lien Chen, Alexandra Brand, Emma L Morrison, Fitz Gerald S Silao, Ursela G Bigol, Fedelino F Malbas, Jeniel E Nett, David R Andes, Norma V Solis, Scott G Filler, Anna Averette, Joseph Heitman

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Abstract

Candida dubliniensis is an emerging pathogenic yeast species closely related to Candida albicans and frequently found colonizing or infecting the oral cavities of HIV/AIDS patients. Drug resistance during C. dubliniensis infection is common and constitutes a significant therapeutic challenge. The calcineurin inhibitor FK506 exhibits synergistic fungicidal activity with azoles or echinocandins in the fungal pathogens C. albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In this study, we show that calcineurin is required for cell wall integrity and wild-type tolerance of C. dubliniensis to azoles and echinocandins; hence, these drugs are candidates for combination therapy with calcineurin inhibitors. In contrast to C. albicans, in which the roles of calcineurin and Crz1 in hyphal growth are unclear, here we show that calcineurin and Crz1 play a clearly demonstrable role in hyphal growth in response to nutrient limitation in C. dubliniensis. We further demonstrate that thigmotropism is controlled by Crz1, but not calcineurin, in C. dubliniensis. Similar to C. albicans, C. dubliniensis calcineurin enhances survival in serum. C. dubliniensis calcineurin and crz1/crz1 mutants exhibit attenuated virulence in a murine systemic infection model, likely attributable to defects in cell wall integrity, hyphal growth, and serum survival. Furthermore, we show that C. dubliniensis calcineurin mutants are unable to establish murine ocular infection or form biofilms in a rat denture model. That calcineurin is required for drug tolerance and virulence makes fungus-specific calcineurin inhibitors attractive candidates for combination therapy with azoles or echinocandins against emerging C. dubliniensis infections.
Original languageEnglish
Pages (from-to)803-819
Number of pages17
JournalEukaryotic Cell
Volume10
Issue number6
DOIs
Publication statusPublished - Jun 2011

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Drug Tolerance
Calcineurin
Candida
Virulence
Echinocandins
Growth
Candida albicans
Azoles
Cell Wall
Infection
Eye Infections
Cryptococcus neoformans
Aspergillus fumigatus
Dentures
Tacrolimus
Biofilms
Combination Drug Therapy
Serum
Drug Resistance
Mouth

Cite this

Chen, Y-L., Brand, A., Morrison, E. L., Silao, F. G. S., Bigol, U. G., Malbas, F. F., ... Heitman, J. (2011). Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. Eukaryotic Cell, 10(6), 803-819. https://doi.org/10.1128/EC.00310-10

Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. / Chen, Ying-Lien; Brand, Alexandra; Morrison, Emma L; Silao, Fitz Gerald S; Bigol, Ursela G; Malbas, Fedelino F; Nett, Jeniel E; Andes, David R; Solis, Norma V; Filler, Scott G; Averette, Anna; Heitman, Joseph.

In: Eukaryotic Cell, Vol. 10, No. 6, 06.2011, p. 803-819.

Research output: Contribution to journalArticle

Chen, Y-L, Brand, A, Morrison, EL, Silao, FGS, Bigol, UG, Malbas, FF, Nett, JE, Andes, DR, Solis, NV, Filler, SG, Averette, A & Heitman, J 2011, 'Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis', Eukaryotic Cell, vol. 10, no. 6, pp. 803-819. https://doi.org/10.1128/EC.00310-10
Chen Y-L, Brand A, Morrison EL, Silao FGS, Bigol UG, Malbas FF et al. Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. Eukaryotic Cell. 2011 Jun;10(6):803-819. https://doi.org/10.1128/EC.00310-10
Chen, Ying-Lien ; Brand, Alexandra ; Morrison, Emma L ; Silao, Fitz Gerald S ; Bigol, Ursela G ; Malbas, Fedelino F ; Nett, Jeniel E ; Andes, David R ; Solis, Norma V ; Filler, Scott G ; Averette, Anna ; Heitman, Joseph. / Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. In: Eukaryotic Cell. 2011 ; Vol. 10, No. 6. pp. 803-819.
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