C. albicans Regulatory Pathways in Oral Candidiasis

Candida albicans is an opportunistic fungal pathogen that is the major cause of oropharyngeal candidiasis (OPC). This disease causes significant morbidity among AIDS patients, even since the advent of highly active antiretroviral therapy. OPC is treated primarily with azole antifungals, but the continuing problem of azole resistance has created a need for new antifungal strategies. Our goal is to identify new C. albicans virulence genes, which will hold promise as targets for these strategies. The ability of C. albicans to produce filamentous cells is associated with pathogenicity, and several C. albicans filamentation regulators have been found through approaches based on filamentation of Saccharomyces cerevisiae (baker's yeast). Filamentation is well defined in S. cerevisiae because of its facile genetic system, but the S. cerevisiae model is limited because it is seldom a pathogen, because it fails to produce true hyphae, and because it fails to respond to several inducers of filamentation for C. albicans. In fact, the major filamentation regulators defined with the S. cerevisiae model, Efg1p and Cph1p, are not essential for infection in a piglet OPC model. Our hypothesis is that there are C. albicans-specific filamentation regulatory genes that will be critical for pathogenicity in OPC, and our immediate objective is to find those genes. We will isolate homozygous random insertion mutations in C. albicans, identify those genes that alter filamentation control, and test defined mutants for pathogenicity in a murine OPC model.