PATHOGENESIS OF OROPHARYNGEAL CANDIDIASIS

La Biomed Res Inst/ Harbor Ucla Med Ctr, Torrance CA

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Abstract

DESCRIPTION: (abstract verbatim) Candida albicans is an opportunistic pathogen that causes an oropharyngeal infection in a large and diverse population of patients. The overall goal of this project is to utilize highly innovative molecular biology strategies to identify as yet undiscovered virulence factors of C. albicans that will be attractive vaccine targets. The driving forces behind this effort are the high prevalence of oropharyngeal candidiasis worldwide, the attractiveness of a vaccine strategy, and the need for treatment approaches that will minimize antifungal resistance. The ability to filament is critical for C. albicans to cause an oropharyngeal infection. However, there is a paucity of knowledge as to which of the signal transduction pathways that regulate filamentation enable C. albicans to cause an oropharyngeal infection. Moreover, there is little information about which virulence factors are regulated by these various pathways. Our central hypotheses are that specific filamentation regulatory pathways that are active in C. albicans when it causes an oropharyngeal infection control the expression of other virulence factors. These virulence factors enable the organism to adhere to, invade and injure host cells during the development of oropharyngeal candidiasis. In addition, the filamentation regulatory pathways control the expression of antigens on the surface of C. albicans, which alter the host inflammatory response that is elicited by the organism. In this project, the applicants will assess the ability of null mutants of C. albicans containing defined defects in the filamentation regulatory pathways to adhere to, invade, injure and stimulate oral epithelial cells in vitro. Based on this assessment, they will select mutants that are highly likely to have reduced virulence. They then determine their ability to cause an oropharyngeal infection in the hyposalivatory rat model. Next, they will construct and use a C. albicans DNA microarray to identify genes encoding potential virulence factors that are expressed by the wild-type strain, but not the mutants with reduced virulence. They will determine the contribution of these candidate genes to virulence by constructing of these second generation mutants with oral epithelial cells in vitro and their virulence in the rat model of oropharyngeal infection.