Sunday, November 24, 2024
11/24/2024
DESCRIPTION: Complications from oropharyngeal candidiasis can be mild to severe, can painful discomfort, and result in impairment of swallowing, and decreased food intake. Colonization of the oral cavity by various Candida species, particularly C. albicans, is a frequent complication among diabetics and immunocompromised patients. The shift of C. albicans from commensal to pathogen is the result of dynamic interactions between the organism and the host environment. Ablation of the first candidate cell surface hydrophobicity (CSH) protein, encoded by the CSH1 gene, resulted in a corresponding loss of CSH under growth conditions that promote the hydrophobic phenotype, and a decrease in adhesion in static and flow assays. Analysis of the CSH1 protein sequence predicts that the protein should be restricted to the cytoplasm due to absence of an N-terminal signal sequence directing insertion into the secretory pathway. A portion of the total cellular pool is detectable on the surface, arguing that a non-traditional export pathway is responsible for the presentation of Csh1p on the cell surface. To test the hypothesis that the Csh1p protein is present on the yeast cell wall via a novel, non-traditional export mechanism, we will address three Specific Aims: 1) Determine whether Csh1p has a specific wall localization and whether forced surface expression has a functional effect on hydrophobicity; 2) Determine whether there is a specific region of Csh1p required for secretion and transport by mutagenesis and chimera analysis in C. albicans and S. cerevisiae; 3) Determine whether previously described secretory mechanisms are involved for Csh1p export by analysis of preexisting secretion mutants in S. cerevisiae and the generation of homologous deletion mutants in C. albicans. The demonstration of a mechanism allowing the surface presentation of Csh1p will further our knowledge of the regulation of Csh1p expression, and expand our long-term goal of understanding the functional role of CSH proteins in affecting cell surface hydrophobicity and their basis in Candida pathogenesis.
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