ArticleEukaryotic cell2013
Cryptococcus neoformans phosphoinositide-dependent kinase 1 (PDK1) ortholog is required for stress tolerance and survival in murine phagocytes.
Article in Eukaryotic cell, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
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- Low Glucose Mediated Fluconazole Tolerance inJournal of fungi (Basel, Switzerland) · 2021Article
- Dangerous Liaisons: Interactions ofPathogens (Basel, Switzerland) · 2020Review
- Hope on the Horizon: Novel Fungal Treatments in Development.Open forum infectious diseases · 2020Review
- Environmental Factors That Contribute to the Maintenance ofMicroorganisms · 2020Review
- PDK1/mTOR Signaling in Myeloid Cells Differentially Regulates the Early and Late Stages of Sepsis.Mediators of inflammation · 2020Article
- Article
- Protein Kinases at the Intersection of Translation and Virulence.Frontiers in cellular and infection microbiology · 2019Review
- Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic FungusmBio · 2017Article
- The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis.Antimicrobial agents and chemotherapy · 2016Article
- Opposing PKA and Hog1 signals control the post-transcriptional response to glucose availability in Cryptococcus neoformans.Molecular microbiology · 2016Article
- Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase.ACS infectious diseases · 2016Article
- Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge.Antimicrobial agents and chemotherapy · 2016Article
- Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles.International journal of pharmaceutics · 2016Article
- High-Throughput Screen inACS infectious diseases · 2016Article
- MacrophageCurrent fungal infection reports · 2014Article
- Stress signaling pathways for the pathogenicity of Cryptococcus.Eukaryotic cell · 2013Review
- Uncoupling of mRNA synthesis and degradation impairs adaptation to host temperature in Cryptococcus neoformans.Molecular microbiology · 2013Article
- A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.Eukaryotic cell · 2013Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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.
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