Candida albicans causes a variety of infectious problems for dental patients. Denture stomatitis and oroesophageal candidiasis are also major problems for AIDS patients. The applicant's recent research on cadidiasis in immunocompetent and immunodeficient gnotobiotic mice has produced new and important findings on the role of thymus-matured and non-thymus-matured T cells and phagocytic cells in resistance to lethal oroesophageal and systemic candidiasis. Their data demonstrates that immunocompetent and some immunodeficient mice manifest resistance to lethal oroesophageal candidiasis. Multiple immune defects (innate and T-cell-mediated) appear to be required for mice to show enhanced susceptibility to lethal oroesophageal candidiasis. The natural susceptibility of these gnotobiotic murine models will help elucidate the cellular basis for resistance to candidiasis at all mucosal surfaces; the model is especially good for studies on oroesophageal candidiasis that minics the disease seen in many dental and AIDS patients. The applicants have demonstrated that CD4epsilon and CD8+ (alphabeta and gammadelta T-cell receptor) T cells, as well as phagocytic cells, play unique roles in resistance to candidiasis at different mucosal sites. This research project will clarify the role that thymus-matured and non-thymus-matured T cells (and their products) and phagocytic cells play in resistance to candidiasis. The applicants will identify the lymphocytes involved in resistance, assess their capacity to restore resistance to oroesophageal candidiasis, and ascertain if therapy with cytokines, produced by immune lymphocytes, can enhance resistance to lethal oroesophageal candidiasis and systemic candidiasis of endogenous origin. This research will not only clarify the role of lymphocytes (and their products) and phagocytic cells in resistance to candidiasis, but it will also provide a rational basis for innovative immunotherapy that will enhance resistance to oroesophageal and systemic candidiasis in patients. This study is also important for the development of safe and effective vaccines that may protect immunocompetent, but not immunodeficient hosts. Restoration and enhancement of immune function may be critical for the effectiveness of anti-Candida vaccines that are now under development.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZDE1-YA (62))
Program Officer
Mangan, Dennis F
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Medical University of South Carolina
Schools of Dentistry
United States
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Balish, Edward (2009) A URA3 null mutant of Candida albicans (CAI-4) causes oro-oesophageal and gastric candidiasis and is lethal for gnotobiotic, transgenic mice (Tgepsilon26) that are deficient in both natural killer and T cells. J Med Microbiol 58:290-5
Westwater, Caroline; Schofield, David A; Nicholas, Peter J et al. (2007) Candida glabrata and Candida albicans;dissimilar tissue tropism and infectivity in a gnotobiotic model of mucosal candidiasis. FEMS Immunol Med Microbiol 51:134-9
Westwater, Caroline; Balish, Edward; Warner, Thomas F et al. (2007) Susceptibility of gnotobiotic transgenic mice (Tgepsilon26) with combined deficiencies in natural killer cells and T cells to wild-type and hyphal signalling-defective mutants of Candida albicans. J Med Microbiol 56:1138-44
Schofield, David A; Westwater, Caroline; Balish, Edward (2005) Divergent chemokine, cytokine and beta-defensin responses to gastric candidiasis in immunocompetent C57BL/6 and BALB/c mice. J Med Microbiol 54:87-92
Balish, Edward; Warner, Thomas F; Nicholas, Peter J et al. (2005) Susceptibility of germfree phagocyte oxidase- and nitric oxide synthase 2-deficient mice, defective in the production of reactive metabolites of both oxygen and nitrogen, to mucosal and systemic candidiasis of endogenous origin. Infect Immun 73:1313-20
Schofield, David A; Westwater, Caroline; Warner, Thomas et al. (2005) Differential Candida albicans lipase gene expression during alimentary tract colonization and infection. FEMS Microbiol Lett 244:359-65
Dolan, Joseph W; Bell, A Cheria; Hube, Bernhard et al. (2004) Candida albicans PLD I activity is required for full virulence. Med Mycol 42:439-47
Schofield, David A; Westwater, Caroline; Balish, Edward (2004) beta-defensin expression in immunocompetent and immunodeficient germ-free and Candida albicans-monoassociated mice. J Infect Dis 190:1327-34
Schofield, David A; Westwater, Caroline; Warner, Thomas et al. (2003) Hydrolytic gene expression during oroesophageal and gastric candidiasis in immunocompetent and immunodeficient gnotobiotic mice. J Infect Dis 188:591-9
Balish, Edward; Warner, Thomas (2002) Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol 160:2253-7

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