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Although orthologs of these kinases have been extensively studied in\n            <jats:named-content content-type=\"genus-species\">S. cerevisiae<\/jats:named-content>\n            , little is known about their function in pathogenic fungi. In this study, we show that\n            <jats:italic>PKH2-02<\/jats:italic>\n            but not\n            <jats:italic>PKH2-01<\/jats:italic>\n            is required for\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            to tolerate cell wall, oxidative, nitrosative, and antifungal drug stress. Deletion of\n            <jats:italic>PKH2-02<\/jats:italic>\n            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.\n            <jats:italic>PKH2-02<\/jats:italic>\n            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\n            <jats:named-content content-type=\"genus-species\">Galleria mellonella<\/jats:named-content>\n            model of low-temperature cryptococcosis, we found that\n            <jats:italic>PKH2-02<\/jats:italic>\n            is also required for virulence in a temperature-independent manner. Consistent with the hypersensitivity of the\n            <jats:italic>pkh2-02<\/jats:italic>\n            \u0394 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\n            <jats:italic>PKH2-02<\/jats:italic>\n            affects the interaction between\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            and phagocytes by decreasing its ability to suppress production of tumor necrosis factor alpha (TNF-\u03b1) and reactive oxygen species. Taken together, our studies demonstrate that Pkh2-02-mediated signaling in\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            is crucial for stress tolerance, host-pathogen interactions, and both temperature-dependent and -independent virulence.\n          <\/jats:p>","DOI":"10.1128\/ec.00235-12","type":"journal-article","created":{"date-parts":[[2012,10,20]],"date-time":"2012-10-20T04:27:12Z","timestamp":1350707232000},"page":"12-22","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":30,"title":["Cryptococcus neoformans Phosphoinositide-Dependent Kinase 1 (PDK1) Ortholog Is Required for Stress Tolerance and Survival in Murine Phagocytes"],"prefix":"10.1128","volume":"12","author":[{"given":"Yeissa","family":"Chabrier-Rosell\u00f3","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly J.","family":"Gerik","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Koselny","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"DiDone","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lodge","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian J.","family":"Krysan","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, University of Rochester, Rochester, New York, USA"},{"name":"Microbiology\/Immunology, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2006.07.001"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328322ffac"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70197-3"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2522"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1843.2012.02150.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e32832fa214"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/604716"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/507891"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2007.05.014"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00041-08"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01273.x"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.04843.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)01528-6"},{"key":"e_1_3_2_15_2","first-page":"143","article-title":"The cAMP\/protein kinase A pathway and virulence in Cryptococcus neoformans","volume":"39","author":"Kronstad JW","year":"2011","unstructured":"KronstadJW HuG ChoiJ. 2011. 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