Oropharyngeal candidiasis is a problem faced by many patients infected with HIV at some point during the course of their illness. Candida albicans, the most common species implicated in AIDS-related candidiasis, causes a spectrum of diseases ranging from """"""""oral thrush,"""""""" invasive mucosal infections and disseminated disease. The ability to transition between yeast and filamentous forms has been shown to be essential for virulence with the filaments invading deep within tissues and yeast form cells forming dense, localized populations. We recently identified a class of bacterially-produced 12-carbon compounds that can inhibit C. albicans hyphal formation. Preliminary experiments suggest that these compounds repress filamentation by disrupting the cAMP signaling component of the hyphal induction pathway. Here we propose to (I) test the hypothesis that C12 compounds inhibit the induction of filamentation by altering the intracellular levels of cAMP, (II) determine if regulatory factors upstream of cAMP in the hyphal induction signaling pathways are affected by C12 compounds, and (III) determine if the reverse hypha-to-yeast transition that is also induced by C12 compound occurs by disrupting the Ras-cAMP-Efg1 signaling pathway. Identification of mechanisms by which small molecules impact morphogenesis pathways may aid in the development of novel therapeutic agents that prevent or limit fungal invasion of tissues. ? ? ?
