Oral candidiasis, caused by the important opportunistic fungal pathogen, Candida albicans, is a sentinel marker of HIV disease progression in immunosuppressed individuals and the cause of severe oral and/or vaginal candidiasis. While the advent of HAART (Highly Active Anti-retroviral Therapy) has decreased the incidence of candidiasis in the HIV-positive population, Candida infection continues to be a significant health problem in treatment failures, non-compliant patients or in countries without adequate treatment options. Recent studies demonstrate that C. albicans is able to produce eicosanoids and related compounds [oxylipins] including prostaglandin E2 (PGE2), although no classic cyclooxygenase genes (COX1 or 2) can be identified in the C. albicans genome. Prostaglandins are potent regulators of host immune and inflammatory responses and prostaglandin E2 reportedly activates HIV-1 LTR (long terminal repeat) transcription, suggesting that elevated levels of PGE2 may stimulate replication of latent virus in T cells. Since elevated levels of PGE2 have been reported in individuals with HIV-1 infection, the molecule could play a promoting role in HIV replication and transmission. We propose to characterize the pathways for PGE2 biosynthesis in C. albicans using DNA microarray expression analyses, enzyme purification and generation of specific mutants. With this project we will set the stage for future studies on the in vivo effects of fungal prostaglandin production. Our studies have several beneficial outcomes: The identification of a new gene/activity responsible for prostaglandin synthesis would provide a novel and potentially highly-specific target for antifungal therapy, which currently has only a limited repertoire of compounds. Moreover, prostaglandin production by C. albicans could locally enhance HIV replication and cell-to-cell viral transmission, thus providing a mechanistic link between opportunistic infection and the retroviral life cycle. Understanding what factors and pathways lead to the induction of fungal PGE2 synthesizing activity will be immediately relevant to understanding how opportunistic pathogens function as cofactors in HIV disease progression. ? ? ?
