Pathogenesis of Candida albicans (CA) and other Candida species involves direct contact of the organism's cell surface with host tissues. Little is known about how Candida species surface macromolecules are modified during initiation of pathogenesis and establishment of infection. However, it has been shown that the cell surface of C. albicans varies in surface hydrophobicity status and that cell surface hydrophobicity (CSH) enhances pathogenicity of C. albicans. Recent studies suggest that CSH status of C. albicans is determined by cell wall protein mannosylation. Biochemical, biophysical, and immunologic studies lead us to propose that modification of the beta-1,2-phosphomannosyl group critically influences exposure of surface hydrophobic proteins (and therefore pathogenesis). In this project, the group will firmly establish the importance of the beta-1,2-phosphomannosyl group in conferring cell surface hydrophobicity. To do so, they will perform the following: 1) test by biochemical means the hypothesis that alteration of the beta-1,2-phosphomannosyl (beta-1,2ManP) group, not necessarily other mannosyl regions, determines CSH; 2) identify and clone the initial synthetic genes for beta-1,2ManP. At least two critical enzymatic steps are involved in synthesis of the beta-1,2ManP group. The first is a phosphomannosyl transferase and the second is a beta-1,2-mannosyltransferase (beta1,2-ManTase); 3) determine the role of the genes in conferring hydrophilicity by phenotypic characterization of the phosphomannosyl transferase and beta-1,2-mannosyltransferase; and 4) establish the general regulation of expression during growth and morphogenesis. From these experiments the PI will demonstrate the critical role of phosphomannosyl transferase and beta1,2-ManTase in determining CSH of C. albicans and influencing cell adhesion. The long-term goal of this research is to dissect the mechanisms of mannosylation of C. albicans cell wall proteins during pathogenesis and determine which ones provide the best targets for anti-Candida species therapy. Regardless of whether expression of the genes is involved in CSH status, elucidation of the genetic mechanism of expression of the beta1,-2ManP group will influence vaccine studies and contribute to the understanding of cell wall protein mannosylation events in pathogenesis.
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