Induction of Epithelial Adhesion and Morphologic Switching by a Single Gene from Candida albicans. • 701

Abstract

Virulence of the yeast Candida albicans has been correlated with its ability to adhere to host epithelium and to undergo a morphologic switch from the yeast phase to various filamentous forms: germ tubes, pseudohyphae and hyphae. The C. albicans gene INT1 encodes a putative adhesin (Int1p) with structural similarity to vertebrate integrins that induces the formation of germ tubes when expressed in the budding yeast Saccharomyces cerevisiae (PNAS 1996). Because multiple adhesins mediate adherence of C. albicans to biologic sites such as epithelial cells, endothelial cells, or platelets, we tested the ability of Int1p to confer adhesive capacity on the non-adherent yeast, S. cerevisiae. We show that expression of Int1p in S. cerevisiae enables these normally non-adherent yeast cells to adhere to mammalian epithelial cells (HeLa cells). This adhesion is Int1p specific: polyclonal antibodies recognizing the EF-hand and RGD motifs of Int1p block yeast cell adhesion to HeLa cells, while pre-immune IgG does not. Epithelial adhesion of S. cerevisiae expressing Int1p approached that of the C. albicans strain from which INT1 was cloned. We also demonstrate that INT1 is involved in the hyphal growth of C. albicans. When both copies of INT1 are disrupted in C. albicans, hyphal growth on solid medium is suppressed; reintegration of INT1 into its native chromosomal locus restores the hyphal phenotype. Thus,INT1 expression is sufficient to induce both epithelial adhesion and a morphologic switch to filamentous growth in S. cerevisiaeand INT1 is required for morphogenesis in C. albicans. INT1 is the first candidal gene implicated in two steps of candidal pathogenesis: adhesion and morphogenesis. By analogy with mammalian integrins, adhesion of C. albicans cells via Int1p to an epithelial ligand may provide a signal that initiates the morphologic switch to hyphal growth. If this is the case, strategies to interrupt the interaction of Int1p with its epithelial ligands may avert the pathologic correlates of morphogenesis in the host.