The incidence of bloodstream infections caused by Candida species has increased dramatically, so that these organisms now account for 10% of all nosocomial bloodstream isolates. Similarly, mucocutaneous candidal infections are becoming increasingly problematic; 80% of patients with the acquired immunodeficiency syndrome (AIDS) have one or more candidal infections. Adherence to epithelial cells is a critical step in the colonization of mucosal surfaces by the organisms and the subsequent establishment of mucocutaneous infection. Analogously, for hematogenous dissemination to occur, the adherence of Candida species to intravascular structures is required for blood-borne organism to egress from the intravascular compartment and invade target organs. Because the mortality rates associated with candidal infections remain disturbingly high despite the presence of antifungal agents with excellent activity against Candida species, optimal therapy will necessitate therapies that increase host resistance to candidal infection (such as blocking adherence), combined with the use of antifungal agents. Since adherence is a critical early step in the development of candidal infections, we will identify and characterize adhesins of Candida albicans by cloning the genes that encode them in Saccharomyces cerevisiae. We already have transformed non-adherent S. cerevisiae with candidal DNA and have isolated a clone that expresses a candidal adhesin. In this proposal we will characterize this adherence gene and its products by constructing mutants of C. albicans in which both alleles of the adherence gene has been deleted. The ability of these mutants to adhere to endothelial and epithelial cells, and their virulence in murine models of hematogenously disseminated and mucosal candidiasis will be determined. The candidal adhesin that we have identified will be purified and its function characterized biochemically; it will be tested further as a potential immunogen. Transformed S. cerevisiae that express additional candidal adhesins will be identified using the diverse selection procedures. These adhesins will be analyzed similarly to the one already identified. The ultimate goal of these investigations is to develop therapeutic strategies to block candidal adherence to host cells. These strategies may then become applicable to both the treatment and prevention of candidal infections.
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