This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with treatment. Many laboratories have shown that endothelial cells play a major role in modifying the inflammatory response. Investigating the interactions of Candida with vascular endothelium has the potential to lead to novel strategies to use endothelial cells to enhance host defense mechanisms. We propose to extend our previous investigations on the molecular mechanisms of the adherence of Candida to endothelial cells, and on the defense mechanisms by which endothelial cells resist damage and invasion by this organism in vitro and in vivo. These studies are aimed at exploring the hypothesis that 1) blocking the adherence of Candida to endothelial cells will prevent their egress from the intravascular compartment, and 2) endothelial cels have mechanisms to resist damage by Candida. These mechanisms are targets to explore for therapeutic up-regulation. These two hypothesis will be evaluated by pursuit of the following specific aims: To determine the role of the ALS1 gene product in mediating the adherence of Candida albicans to human vascular endothelial cells. To determine the mechanisms by which endothelial cells escape damage when C. Albicans is killed by neutrophils on endothelium. To determine whether the immunomodulators and candidal virulence factors identified in our in vitro experiments are expressed at sites of candidal infection in humans with hematogenously disseminated candidiasis.