SIGNALING COMPLEXES AND THE 14-3-3 PROTEIN IN CANDIDA

Louisiana State Univ Hsc New Orleans, New Orleans LA

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Abstract

DESCRIPTION: (Adapted from Applicant's Abstract) Fungal infections have increased dramatically in recent years due to the onset of AIDS and improved treatment of immunosuppressed individuals. Among AIDS patients, the most prevalent mycotic disease is mucosal infection due to Candida albicans. However, the molecular events which occur during the pathogenesis of C. albicans are not well defined. For example, upon contact with mammalian tissue and initiation of infection, C. albicans switches between growth forms. Therefore, genes involved in environmental response, cell morphology, and cell cycle must be coordinately regulated when the fungus interacts with the host. Using differential display reverse transcription technology in conjunction with a novel adherence assay, the P.I. identified BMH1. This gene is differentially regulated after adherence to a human esophageal cell line grown in an extracellular matrix. BMH1 exists as a single copy gene in C. albicans and encodes a 14-3-3 protein motif that is highly homologous to other 14-3-3 genes of the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. The expression of the C. albicans homolog significantly decreases after exposure to the extracellular matrix. Because 14-3-3 proteins are important for the activation of signaling genes in mammals as well as pseudohyphal induction, normal bud development, and cell cycle control in yeasts, investigations are proposed to examine the role of C. albicans BMH1 in signaling, morphogenesis, and cell cycle control. The present proposal intends to construct null mutants and reconstituted strains to functionally characterize the BMH1 gene and its role in these events. The yeast two-hybrid system and gene fusion constructs will be created to detect protein interactions with BMH1. Finally, the P.I. proposes to assess if Bmh1p is involved in pathogenesis using an oral candidiasis model. It is hoped that the results of this study will lead to the identification of potential antifungal targets.