Invasive aspergillosis is an increasingly common, usually fatal infection affecting growing numbers of immunocompromised patients. Predisposition to progressive invasive aspergillosis has been associated with specific factors. These include neutropenia, most often related to antineoplastic chemotherapy, or abnormalities in the host inflammatory response due to extended, high dose corticosteroid therapy, post-transplantation immunosuppression, or the acquired immunodeficiency syndrome (AIDS). Neutrophils (PAN) and macrophages are major host effector cells responsible for clearing the various forms of Aspergillus organisms from host tissues. However, recent data suggest key roles for other cell types besides phagocytes in the types of intravascular inflammatory responses that must prevent or contain progressive aspergillosis. The pathogenesis of invasive aspergillosis is marked by dramatic invasion of blood vessel walls, with thrombosis and hemorrhagic infarction. Platelets directly mediate pivotal components of intravascular inflammation and also are critical modulators of phagocytic and vascular endothelial cell function. Prolonged neutropenia is cited as a dominant associated risk factor for invasive aspergillosis, but almost all such patients have concomitant thrombocytopenia. Recent reports by others note avid platelet adherence to Candida albicans as well as candidacidal activity of a platelet granule-associated cationic peptide. Our data further show that Aspergillus fumigatus hyphae and resting or swollen conidia adhere to and activate human platelets. Platelets alone predominantly induce significant but reversible damage to functional cell walls. Some fungicidal activity occurs in the process, but is limited in the absence of other inflammatory cells. However, PAN and platelets combined have enhance fungicidal effects. Therefore, we plan to define: (a) the platelet and fungal surface constituents mediating adherence and platelet activation; (b) the specific mechanisms and consequences of fungal damage by platelets; and (c) the interactive effects of human platelets, PAN, monocytes, and/or endothelial cells on killing of A. fumigatus hyphae and conidia. Our prior data show that human vascular endothelial cells endocytose but do not kill A. fumigatus hyphae or conidia, so we will also study the interactive effects of platelets, phagocytes, and endothelium on fungal cell survival as well as inflammatory host cell damage related to platelet and leukocyte activation. The long-term objective is to increase understanding of the normally potent host defenses that prevent or contain invasive aspergillosis in the absence of immunosuppression. Ultimately, this may improve measures to prevent and/or treat this now too often lethal infection.
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