Journal article
Cryptococcus neoformans Phosphoinositide-Dependent Kinase 1 (PDK1) Ortholog Is Required for Stress Tolerance and Survival in Murine Phagocytes
Eukaryotic cell, Vol.12(1), pp.12-22
01/2013
DOI: 10.1128/EC.00235-12
PMCID: PMC3535849
PMID: 23087368
Abstract
Cryptococcus neoformans PKH2-01 and PKH2-02 are orthologous to mammalian PDK1 kinase genes. Although orthologs of these kinases have been extensively studied in S. cerevisiae, little is known about their function in pathogenic fungi. In this study, we show that PKH2-02 but not PKH2-01 is required for C. neoformans to tolerate cell wall, oxidative, nitrosative, and antifungal drug stress. Deletion of PKH2-02 leads to decreased basal levels of Pkc1 activity and, consequently, reduced activation of the cell wall integrity mitogen-activated protein kinase (MAPK) pathway in response to cell wall, oxidative, and nitrosative stress. PKH2-02 function also is required for tolerance of fluconazole and amphotericin B, two important drugs for the treatment of cryptococcosis. Furthermore, OSU-03012, an inhibitor of human PDK1, is synergistic and fungicidal in combination with fluconazole. Using a Galleria mellonella model of low-temperature cryptococcosis, we found that PKH2-02 is also required for virulence in a temperature-independent manner. Consistent with the hypersensitivity of the pkh2-02Δ mutant to oxidative and nitrosative stress, this mutant shows decreased survival in murine phagocytes compared to that of wild-type (WT) cells. In addition, we show that deletion of PKH2-02 affects the interaction between C. neoformans and phagocytes by decreasing its ability to suppress production of tumor necrosis factor alpha (TNF-α) and reactive oxygen species. Taken together, our studies demonstrate that Pkh2-02-mediated signaling in C. neoformans is crucial for stress tolerance, host-pathogen interactions, and both temperature-dependent and -independent virulence.
Details
- Title: Subtitle
- Cryptococcus neoformans Phosphoinositide-Dependent Kinase 1 (PDK1) Ortholog Is Required for Stress Tolerance and Survival in Murine Phagocytes
- Creators
- Yeissa Chabrier-Roselló - Departments of PediatricsKimberly J Gerik - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USAKristy Koselny - Departments of PediatricsLouis DiDone - Departments of PediatricsJennifer K Lodge - Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USADamian J Krysan - Departments of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Eukaryotic cell, Vol.12(1), pp.12-22
- DOI
- 10.1128/EC.00235-12
- PMID
- 23087368
- PMCID
- PMC3535849
- NLM abbreviation
- Eukaryot Cell
- ISSN
- 1535-9778
- eISSN
- 1535-9786
- Publisher
- American Society for Microbiology
- Language
- English
- Date published
- 01/2013
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093345502771
Metrics
13 Record Views