The studies are focused on enhancing the host defense mechanisms against the increasingly important nosocomial pathogen, C albicans. Using monolayers of human vascular endothelial cells as a model for the intravascular compartment, mechanisms have been examined by which candidal organisms adhere to the endothelial cells and escape from the blood vessels to infect target organs. During the current project period a gene in C albicans, ALSI, was identified that is highly likely to encode a dominant adhesin to human vascular endothelial cells. Based on the magnitude of the adherence its gene product confers and its homology with the alpha agglutinin of S. cerevisiae, this gene is a particularly promising candidate for being a dominant adhesin in C albicans. During the proposed project period, it is planned to perform in-depth characterization of the role of ALS1 in the adherence of C albicans to human vascular endothelium. Our in vitro studies have shown that C albicans activates the endothelial cells to express the leukocyte adhesion molecules, E-selectin, intercellular adhesion molecule 1 (ICAM-1) and to secrete interleukin 6 (IL-6), IL-8. These mediators likely recruit neutrophils to endothelial cells infected with C. albicans. When neutrophils are added to endothelial cells infected with C. albicans, in vitro, the endothelial cells escape damage by both the neutrophils and the organisms. In the proposed project period, in depth investigations will be performed on the mechanisms by which endothelial cells escape damage. These investigations will provide fundamental information regarding the mechanism by which bystander host cells are protected during the inflammatory response. To establish in vivo correlations in humans with our in vitro studies, a unique and invaluable resource for data and human specimen collection will be utilized. This resource is the National Institutes of Health Mycosis Study Group. Immunohistochemical studies will be performed on clinical specimens obtained from patients with hematogenously disseminated candidiasis to establish in vivo correlations with in vitro findings. In vivo correlations that will be investigated are: 1) Specific candidal adhesins mediating the attachment of this organism to endothelial cells; and 2) mechanisms through which endothelial cells protect themselves from candidal injury by recruiting neutrophils.
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