Identification of potential cell‐surface proteins in Candida albicans and investigation of the role of a putative cell‐surface glycosidase in adhesion and virulence

• Published in: Yeast (Chichester, England) Vol. 21; no. 4; pp. 285 - 302
• Main Authors: Alberti‐Segui, Christine, Morales, Arturo J., Xing, Heming, Kessler, Marco M., Willins, Debra Aker, Weinstock, Keith G., Cottarel, Guillaume, Fechtel, Kim, Rogers, Bruce
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-03-2004
• Subjects: adhesion; Amino Acid Sequence; Animals; Candida albicans; Candida albicans - enzymology; Candida albicans - genetics; Candida albicans - pathogenicity; Candida albicans - physiology; Cell Adhesion - physiology; Cell Wall - chemistry; Cell Wall - enzymology; cell‐surface factors; cell‐wall proteins; Gene Deletion; Genotype; glycosidases; Glycoside Hydrolases - genetics; Glycoside Hydrolases - metabolism; Humans; Mammals; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Phenotype; Proteome; Sequence Alignment; Sequence Homology, Amino Acid; Virulence
• ISSN: 0749-503X; 1097-0061
• DOI: 10.1002/yea.1061

Cell‐surface proteins are attractive targets for the development of novel antifungals as they are more accessible to drugs than are intracellular targets. By using a computational biology approach, we identified 180 potential cell‐surface proteins in Candida albicans, including the known cell‐surface adhesin Als1 and other cell‐surface antigens, such as Pra1 and Csa1. Six proteins (named Csf1‐6 for cell‐surface factors) were selected for further biological characterization. First, we verified that the selected CSF genes are expressed in the yeast and/or hyphal form and then we investigated the effect of the loss of each CSF gene on cell‐wall integrity, filamentation, adhesion to mammalian cells and virulence. As a result, we identified Csf4, a putative glycosidase with an apparent orthologue in Saccharomyces cerevisiae (Utr2), as an important factor for cell‐wall integrity and maintenance. Interestingly, deletion of CSF4 also resulted in a defect in filamentation, a reduction in adherence to mammalian cells in an in vitro adhesion assay, and a prolongation of survival in an immunocompetent mouse model of disseminated candidiasis. A delay in colonization of key organs (e.g. kidney) was also observed, which is consistent with a reduction in virulence of the csf4‐deletion strain. These data indicate a key role for extracellular glycosidases in fungal pathogenesis and represent a new site for therapeutic intervention to cure and prevent fungal disease. Copyright © 2004 John Wiley & Sons, Ltd.