INTERACTION OF HISTOPLASMA CAPSULATUM WITH HUMAN MACROPHAGES

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Histoplasmosis is a pulmonary infection acquired by inhalation of microconidia of Histoplasma capsulatum (Hc) from natural sources. The inhaled conidia deposit in the lung within the terminal brochioles and alveoli, and undergo transformation into the pathogenic yeast phase. The primary disease is generally self-limited, but occasionally evolves into a chronic cavitary form. In experimental animals, Hc yeasts can be detected in infected areas of the lung within 36 hr after inhalation of the conidia, and are present exclusively in macrophages (Mphi), within which the yeasts multiply. Presumably, destruction of Hc conidia or yeasts by alveolar Mphi during the earliest phase of the infection would abrogate the establishment of disease. However, the events involved in the transformation of conidia to yeasts are obscure, and it is not clear whether transformation occurs intra- or extracellularly. In addition, the capacity of human alveolar Mphi to kill Hc conidia or yeasts upon initial encounter is unknown, as is the fungicidal mechanism of macrophages activated by specific cell-mediated immunity. The objectives of this research project are to examine in detail the interaction of Hc with human monocyte/macrophages. The specific aims of the project are: 1) To determine the intracellular fate of Hc conidia and yeasts upon phagocytosis by human monocytes, cultured human Mphi, and human alveolar Mphi; to define cellular mechanisms that mediate antifungal activity against Hc; and to identify the cytokines that are required to activate Mphi antifungal activity. 2) To identify and purify the component(s) on Hc yeasts and conidia that are recognized by the LFA-1, CR3, p150, 95 adhesion receptors on Mphi. 3) To determine if Hc binding to Mphi LFA-1, CR3, p150, 95 induces activation of protein kinase C and/or phosphorylation of specific membrane or cytosolic proteins.