Candida are now the fourth most common organisms recovered from blood of hospitalized patients and comprise 10% of the blood isolates. Although potent antifungals exist, mortality rates from candidal septicemia remain nearly 50%. Because of this unacceptably high death rate, we have studied strategies for enhancing host defenses against Candida. Using monolayers of human vascular endothelial cells in vitro, we have examined the mechanisms by which Candida adhere to endothelial cells and escape from the vascular compartment to infect visceral organs. During the past grant period, we found that Candida stimulates endothelial cells to produce specific prostaglandin mediators of inflammation (PGI2, PGF2alpha, PGE2) in vitro, by enhancing arachidonic acid mobilization and synthesis of cyclooxygenase. We found also that INF-gamma induces endothelial cells to resist candidal damage. Additionally, we characterized the human complement receptor (CR)-like molecules on C. albicans further by defining their antigenic similarities to the human CR2 and CR3. We inhibited candidal adherence to endothelial cells with candidal extracts containing these receptors, supporting their role as adhesions. Finally, we extracted a cationic peptide from platelets that has potent anti-candidal activity and may be important in host defense against Candida. Since adherence is the first step in endothelial cell invasion, we intend to clone the adherence genes of Candida in Saccharomyces cerevisiae and transform non-adherent Saccharomyces into adherent strains. From these DNA transformation studies, the gene product/s responsible for adherence of Candida can be identified and strategies for blocking adherence developed. To devise strategies to improve host defenses against Candida, we will investigate how INF-gamma induces endothelial cells to resist candidal damage and we will determine whether GM-CSF, and IL1-beta have direct protective effects on endothelial cells. We will develop strategies to increase the combined capacity of neutrophils and endothelial cells to kill Candida by priming both cell types with the immunomodulators INF-gamma, GM-CSF, and IL-1beta. Additionally, we will elucidate the mechanisms by which activated neutrophils may induce cytoprotective responses in endothelial cells.
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