Acquired immunodeficiency syndrome (AIDS) is an immunoregulatory disorder characterized by the presence of Kaposi's sarcoma or opportunistic infections. CD4+ T cells and mononuclear phagocytes are the target cells for the human immunodeficiency virus (HIV), the etiologic agent of AIDS. Monocyte/macrophages are a major reservoir of HIV and, therefore, a critical concern for the host is the functional capacity of monocyte/macrophages from HIV+ individuals to destroy opportunistic pathogens. Histoplasma capsulatum (Hc) is a dimorphic fungal pathogen of worldwide importance that causes a broad spectrum of disease activity. Although the course of infection is mild in most immunocompetent individuals, disseminated histoplasmosis is seen with increasing frequency as a complication of AIDS, particularly in areas where Hc is endemic. AIDS patients with disseminated histoplasmosis have a high rate of relapse even after apparently successful therapy with amphotericin B. The pulmonary alveolar monocyte/macrophage (AM) is the first line of defense following inoculation of Hc into the respiratory tract. These cells initially encounter inhaled microconidia and subsequently the transformed yeasts. The sequence of events that occur from the time that conidia enter the alveolar spaces in the lung until the appearance of numerous replicating yeasts in AN is unclear. An impairment in AM function during the initial contact with Hc could be fatal to the host. The goal of the proposed study is to gain a better understanding of the interaction of Hc yeasts and conidia with normal human AN, and with AN from patients with HIV infection.
The specific aims of this proposal are: l) to quantify the capacity of AM from HIV+ individuals to bind and ingest Hc yeasts and conidia compared to AM from HIV- individuals; 2) to determine if AM from HIV+ individuals permit more rapid conversion of Hc conidia into the pathogenic yeast phase or permit more rapid multiplication of yeasts than normal AM; 3) to quantify and compare the capacity of cytokines, extracellular matrix proteins, and surfactant protein A (SP-A) to regulate the intracellular growth of Hc yeasts in normal vs. HIV-infected AM; and 4) to determine the roles of iron, the vacuolar ATPase (V-ATPase), pH, and phago-lysosomal fusion in regulating the intracellular growth of Hc yeasts in HIV- vs. HIV+ AM.
