Title

Mechanisms of oral mucosal cell proinflammatory cytokine responses to Candida albicans

Date of Completion

January 2007

Keywords

Biology, Microbiology|Health Sciences, Dentistry|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Oropharyngeal candidiasis is commonly preceded by reduction in T cell number and function in patients with HIV infection or under immunosuppressive therapy. Although these groups of patients are susceptible to oropharyngeal candidiasis, hematogenous dissemination of infection is extremely uncommon, suggesting that local oral mucosal cells might deliver activation signals to innate immune effector cells. As the first cells to interact with C. albicans, epithelial and endothelial cells represent the first line of defense against invasive infection. Production of proinflammatory cytokines by these cells in response to Candida albicans (C. albicans) plays a critical role in the early activation of immune cells and clearance of the organism. Our studies investigated the interactions between oral mucosal cells and C. albicans, and the mechanisms by with local non-immune mucosal cells respond to C. albicans by mounting a proinflammatory cytokine response. We found that C. albicans transformation into true hyphae enhances the adhesive interaction of C. albicans with oral epithelial cells and increases the ability of the organism to trigger strong proinflammatory responses. Moreover, we also found that the ability of C. albicans to invade host cells and tissues affects the intensity and composition of the proinflammatory cytokine response. Overall, highly invasive strains triggered higher levels of proinflammatory cytokines in host cells than invasion-deficient mutants. Finally, we demonstrated that C. albicans invades the oral mucosa both via an intracellular pathway and via an intercellular pathway by promoting Sap5p-mediated degradation of E-cadherin in epithelial adherens junctions, suggesting that this fungus uses more than one mechanism to invade tissues. These data provide a better understanding of the host response and pathogenesis of oral mucosal Candida infection. ^