MOLECULAR PATHOGENESIS OF ORAL CANDIDIASIS

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Our long range objective is to understand the molecular interactions between the fungal pathogen, Candida olbicans and humans infected with HIV. Identification of key molecules contributing to the commensal and pathogenic status in healthy and immunocomprised hosts, respectively, will provide a basis for characterizing the dynamic interactions of opportunistic candidal infections in the oral cavity. Essentially all C.albicans strains have the innate capacity to cause disease under permissive host conditions. Either commensal colonization or invasive proliferative infection is accompanied by the expression of different elements of the fungal gene repertoire. Despite characterization in the laboratory setting of putative virulence determinants, an understanding of how these are regulated and expressed in the progression from commensal to fulminant infections has not emerged. Indeed, several determinants, notably the secreted aspartyl proteinases, display a complex pattern of gene expression regulated by a constellation of environmental and genetic factors. As a result, the correlation between laboratory studies and pathogenesis in oral candidiasis remains to be established. Our immediate objective will be to characterize fungal and host molecules in situ in pseudomembranous and erythematous lesions. Patient biopsies will be ussed to prepare cDNA and subtraction cDNA libraries of fungus and host; biopsies of uninvolved adjacent tissue will serve as controls. Clones of sequences expressed at the lesional site will be classified by size, and characterized by in situ hybridization in comparable biopsies. These studies should reveal those mRNAs expressed by fungal pathogen, and host peithelial and infiltrating cells. 2) Lesion-specific cDNAs will be DNA sequenced, compared with databanks and pursued in accordance with their putative function; Candida specific clones of unkonwn function will be characterized by analysis of null mutant phenotypes and those of human origin by tissue specific expression and correlation with host immune and HIV status. 3) We will analyze the patterns of expression of putative adherence ligands and SAP mRNAs in biopsies to establish the relevance of these putative virulence factors in candidal lesions. These studies should result in the indentification and characterization of potential virulence and pathogenesis determinants in oral candidiasis and provide the first description of the cellular microbiology of oral lesions.