Calcineurin controls hyphal growth, virulence, and drug tolerance of Candida tropicalis.
Candida tropicalis, a species closely related to Candida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. Like C. albicans and Candida dubliniensis, C. tropicalis is able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear in C. tropicalis. Recently, echinocandin- and azole-resistant C. tropicalis isolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of the C. tropicalis genes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis in C. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions in C. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance in C. tropicalis.
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan ychen28@ntu.edu.tw heitm001@duke.edu.
Ying-Lien
YL
Chen
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan.
Shang-Jie
SJ
Yu
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan.
Hsin-Yu
HY
Huang
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan.
Ya-Lin
YL
Chang
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
Virginia N
VN
Lehman
Department of Microbiology and Parasitology, University of Perpetual Help-Dr. Jose G. Tamayo Medical University, Biñan, Laguna, Philippines.
Fitz Gerald S
FG
Silao
Environment and Biotechnology Division, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Philippines.
Ursela G
UG
Bigol
Department of Microbiology and Parasitology, University of Perpetual Help-Dr. Jose G. Tamayo Medical University, Biñan, Laguna, Philippines National Institutes of Health-Philippines, University of the Philippines, Manila, Philippines.
Alice Alma C
AA
Bungay
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
Anna
A
Averette
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA ychen28@ntu.edu.tw heitm001@duke.edu.
Joseph
J
Heitman
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D041022:Candida tropicalis / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D025301:Hyphae / Q000254:growth & development*; D055666:Lipopeptides / Q000494:pharmacology; D000077551:Micafungin; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D014157:Transcription Factors; D019703:Calcineurin; D000077551:Micafungin