Candidiasis, aspergillosis, cryptococcosis and mucormycosis are the most common opportunistic mycoses, and have been recognized with increasing frequency in recent years. In our past work, we developed new methods for quantitating damage to hyphae, the tissue invasive forms of Candida, Aspergillus and Rhizopus. With in vitro systems, we have continued to define some of the oxidative and nonoxidative mechanisms involved in killing of fungi by human and murine neutrophils, monocytes and macrophages. Utilizing murine models of respiratory-acquired mycoses which we developed, we compared factors related to the pathogenesis of aspergillosis and mucormycosis. As these mycoses prominently include vascular invasion as a major factor in progression, we have begun studies on interactions between fungi, vascular endothelial cells, and other host cells. We now intend to continue this combined approach with four major areas of emphasis: 1) to determine the relative abilities of different cell types (alveolar, peritoneal and tissue macrophages, neutrophils, monocytes, natural killer cells, and antibody-dependent killer cells) to mediate killing of hyphal and other forms of Aspergillus, Rhizopus and Candida, as well as mechanisms of cell activation and killing by defining events occurring at the leukocyte surface during activation stimulated by contact with hyphae (compared with intracellular events occurring within phagocytic vacuoles, after complete ingestion of particles - e.g., comparison of activation by Candida albicans hyphae vs. blastospores); 2) to further define surface features of fungi which are involved in attachment to and activation of neutrophils utilizing characterized fungal products as well as existing monoclonal antibodies to neutrophil surface features; 3) to continue studies of the role of endothelial cells in the pathogenesis of these mycoses using systems we have developed for in vitro tissue culture, as well as whole vessel, in situ perfusion to monitor interactions of fungi with endothelial and other host cells (leukocytes and platelets); and 4) interacting with the three above aims relating to in vitro studies, to continue in vivo studies of opportunistic mycoses to define the relative importance of specific host defects in the pathogenesis of individual mycoses (e.g., aspergillosis vs. mucormycosis), and the reasons for the association of one or another fungal infection with a particular predisposing factor (e.g., diabetes mellitus, corticosteroids, etc.).
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