Candida species are among the most common causes of hospital-acquired infections. Candidiasis is associated with substantial morbidity, mortality, and high hospitalization costs. Ongoing problems with antifungal efficacy and resistance make the development of novel therapeutic approaches against candidiasis highly attractive. Such approaches include a Candida vaccine, and passive immunotherapy with anti-Candida antibodies. We have discovered that the Candida albicans protein, Agglutinin-like sequence-1 (Als1p), is a potent adhesin for human vascular endothelial cells. We have also found that additional members of the Als protein family mediate attachment to distinct profiles of host substrates, including fibronectin, collagen, epithelial cells and endothelial cells. Our experiments have shown that immunization with recombinant Als1p, and antibodies to the N-terminus of the protein protect mice against lethal intravenous challenge with C. albicans. Importantly, sera from mice immunized with Als1p blocks C. albicans adherence to endothelial cells in vitro. Collectively, these results identify the Als protein family as a promising target for therapeutic strategies. In our proposed experiments, we will 1) define the precise domains of Als proteins that mediate endothelial cell binding;2) identify the endothelial cell ligand(s) which are bound by these Als proteins, and 3) determine the in vivo expression profiles of ALS genes, and define the role of Als proteins in governing tissue tropism. These studies will initially focus on Als1p and subsequently be extended to other Als proteins. The results of the proposed experiments will advance basic understanding of C. albicans interactions with the host at the receptor-ligand level. The results of these studies will provide the foundation for the future development of novel therapeutic approaches to block candidal adherence and enhance host defense.