title: Identification of potential cell-surface proteins in Candida albicans and investigation of the role of a putative cell-surface glycosidase in adhesion and virulence.
abstract: 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.
authors.affiliation: Genome Therapeutics Corporation, Waltham, MA 02453, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Alberti-Segui
authors.forename: Arturo J
authors.initials: AJ
authors.lastname: Morales
authors.forename: Heming
authors.initials: H
authors.lastname: Xing
authors.forename: Marco M
authors.initials: MM
authors.lastname: Kessler
authors.forename: Debra Aker
authors.initials: DA
authors.lastname: Willins
authors.forename: Keith G
authors.initials: KG
authors.lastname: Weinstock
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cottarel
authors.forename: Kim
authors.initials: K
authors.lastname: Fechtel
authors.forename: Bruce
authors.initials: B
authors.lastname: Rogers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002176:Candida albicans / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002473:Cell Wall / Q000737:chemistry* / Q000201:enzymology; D017353:Gene Deletion; D005838:Genotype; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008322:Mammals; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010641:Phenotype; D020543:Proteome; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014774:Virulence
chemical_list: D008565:Membrane Proteins; D020543:Proteome; D006026:Glycoside Hydrolases