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, Hc may produce progressive disseminated infections in individuals immunocompromised by hematologic malignancies, cytotoxic therapy, or in individuals with the acquired immunodeficiency syndrome (AIDS). Infection with Hc is acquired by inhalation of microconidia into the pulmonary alveoli. The conidia convert into the pathogenic yeast phase, and yeasts are phagocytized by alveolar macrophages (AM). Dividing yeasts destroy the AM, and then they are ingested by other AM, and by inflammatory neutrophils and macrophages (M-phi). Repetition of this cycle leads to dissemination of Hc via blood and lymphatics. Maturation of specific cell-mediated immunity (CMI) against Hc activates M-phi to halt yeast proliferation with gradual resolution of the disease process. ? ? Although, dendritic cells (DC) are the most potent antigen-presenting cells (APC) of the immune system, and are critical for the induction of CMI, their role in host defense against fungi has been largely ignored. The overall goal of the proposed research is to understand the biology and biochemistry of the interaction of Hc with DC, and to characterize the role of DC in the induction of protective immunity to Hc. The major objectives of the proposal are: 1) To determine if murine lung DC ingest and restrict the conversion of Hc conidia into yeasts. Specifically we will determine if lung DC phagocytose Hc conidia, determine if recognition is via VLA-5, determine the intracellular fate of conidia, identify the cytokines produced by Hc-infected DC, and determine why Hc is recognized by different receptors on M-phi and DC. 2) To identify the functional correlates for antigen presentation between Hc-infected DC and T cells with respect to T cell proliferation, cytokine production, and the requirement for co-stimulatory molecules, and to determine if DC-Hc-T cell interaction produces cytokines that activate M-phi anti-histoplasma activity. 3) To determine if Hc antigen-pulsed DC confer protective immunity in a murine model of pulmonary histoplasmosis, and to define the immunologic parameters of protective immunity in immunocompetent and immunocompromised mice. The results of these studies should provide significant insight into the pathogenesis of histoplasmosis and aid in the design of novel vaccine strategies for the prevention of disease.
