In oropharyngeal candidiasis a breakdown of the mucosal innate defenses and decreased polymorphonuclear cell number or function result in the transition from oral commensalism to mucosal infection. The overall goal of this competitive renewal is to continue studies on the oral mucosal inflammatory responses to Candida albicans and the regulatory role of these responses on the function of innate immune cells and Candida clearance. Data from our laboratory indicate the existence of a cytokine communication network between oral epithelial cells, fibroblasts and innate immune cells with potentially important consequences in the inflammatory response to this pathogen and the clearance of this infection in vivo. So far we have studied these interactions between multiple cell types using a single cell system approach. To overcome some of the imitations associated with single cell culture systems we propose to use an artificial tissue culture system, incorporating saliva, oral epithelial cells and fibroblasts, in an attempt to mimic the oral masticatory mucosa and submucosa. We will also incorporate an immunological component in a modification of this system by adding peripheral blood neutrophils and examining their migratory and candidacidal activities. The novelty and additional benefit from this approach is that the mucosal-submucosal cell dialogue can be monitored simultaneously during infection, taking into account complex cell-cell contact interactions and interactions that are carried out via secreted cytokines. Using these novel tissue culture approaches we propose to study: a) the role of proinflammatory cytokines in neutrophil transepithelial migration and Candida clearance; b) the role of germination-dependent gene products in C. albicans virulence; and c) the virulence of C. glabrata in a mono-infection and co-infection models. Identification of candidate cytokine effectors which are involved in the innate immune cell activation and C. albicans genes which promote invasive infection will provide novel therapeutic targets within the C. albicans-oral mucosal response framework.
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