Oropharyngeal and esophageal candidiasis are among the most frequent opportunistic fungal infections observed in HIV+ and AIDS patients, occurring in the majority of patients. The pathogenesis is complex and probably involves multiple host factors that include loss of cell mediated immunity and altered phagocytic cell activity. Relevant features of Candida albicans, the most frequent cause of oral candidiasis in HIV- infected patients, are persistence in the gastrointestinal mucosa and invasiveness in the presence of diminished host defenses. Although C. albicans is sensitive to antifungal drugs, treatment over long periods of time are required, and isolates from HIV infected patients may be more resistant than other isolates. New approaches towards preventing or managing oral candidiasis are needed. A feature of C. albicans growth that is correlated with pathogenicity in the oral cavity is the ability to transform from budding to filament-extending growth. Filamentous forms adhere more readily to buccal epithelial cells than budding yeasts, and histologically are a prominent feature of invasion of the mucosa. Knowledge of the molecular events that transform C. albicans to the pathogenic filamentous form, as well as detailed investigations of the hyphal surface at the molecular level are necessary for understanding the pathogenesis of oral candidiasis. The purpose of this research is to identify specific proteins of C. albicans hyphal surfaces using a molecular genetic approach, and, to determine the mechanisms leading to surface protein gene expression. By studying the genetic organization and mRNA expression of hyphal-specific surface protein genes, important information on the regulation of yeast to hyphal morphogenesis will be obtained. Finally, experiments are proposed that will define the role of hyphal surface proteins in hyphal growth using techniques that will selectively disrupt a hyphal surface protein gene. These goals will be accomplished using a partial cDNA clone termed HWP1 that was identified by screening a cDNA library with antibodies to hyphal growth forms. HWP1 mRNA is abundant in C. albicans hyphae but is absent in yeast. The open reading frame predicted by HWP l encodes a novel proline and glutamine rich protein that is largely composed of a repetitive amino acid motif reminiscent of surface proteins of Plasmodia, and other lower eucaryotes, that are important for attachment to host cells and elicit protective immunity. These studies are important in that they involve a major, immunodominant surface protein that is implicated in adherence and invasion; the hallmarks of C. albicans. This protein, hwp1, does not resemble any previously described C. albicans surface protein and, as such, will extend the current view of the C. albicans surface and its interaction with the host. Similarly, the molecular events leading to the expression of hwp l will advance the understanding of general mechanisms leading to the pathogenic hyphal form. The research presented in this proposal will provide new insight into the determinants of pathogenicity that lead to the high frequency of oral candidiasis in HIV+ and other immunocompromised patients.
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