This Program aims to define the range of critical responses by which major types of leukocyte effector cells combat distinct, serious mycoses, facilitating collaborative insights into comparative mechanisms of effector response patterns to disparate target fungi with differing susceptibilities to varying leukocyte products. The major objective of Project # 1 (R.D. Diamond and F.R. Sullivan, co-investigators) is to determine the bases for preliminary results indicating disparate effects of human cytokines on killing of Candida albicans hyphae by neutrophils (PMN), even though three cytokines (interferon-gamma, tumor necrosis factor-alpha and granulocyte- macrophage colony stimulating factor) all enhance the PMN respiratory burst primarily required for killing these organisms. Project # 2 (E.H. Smail) aims to characterize biochemically and functionally a product of C. albicans hyphae which inhibits PMN superoxide release and degranulation but not chemotaxis induced by a wide range of agonists, without altering responses to phorbol myristate acetate. Project # 3 (S.M. Levitz) addresses the unique interactions with macrophages of Cryptococcus neoformans yeasts and the role of its capsular polysaccharide in its interactions with both host serum opsonins and phagocytic cells, particularly effects on killing and on specific cellular signal transduction response patterns to stimulation, which will be determined in single cells and cell populations upon activation via single or multiple defined macrophage membrane receptors. Project # 4 (A.M. Sugar) addresses the process by which macrophages act as major effector mediating defenses controlling blastomycosis, aiming to define receptor activation mechanisms, signal transduction pathways, and ultimate responses which determine divergent fungicidal responses against conidia and yeasts, as well as the mechanisms by which cytokines augment inefficient killing by unstimulated macrophages. Project # 5 (W.E. Hauser) focuses on defining the receptor- mediated signal transduction pathways responsible for triggering and controlling direct inhibition and/or killing of C. neoformans and indirect release of mediators by NK cells to augment neutrophil candidacidal effects. Three Core units are designed to provide coordinated facilities for all projects in analysis of individual cell responses, surface receptor and lipid metabolic changes related to signal transduction, and coordination of leukocyte supplies from normal and immunodeficient donors.
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