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 where they convert into the pathogenic yeast phase. Maturation of specific cell-mediated immunity against Hc requires a complex interaction between dendritic cells (DC), macrophages, and T cells that eventually leads to activation of macrophages and resolution of the disease process. We hypothesize that Hc replication in macrophages of the lung is the basis for the ability of Hc to disseminate, that the ability of DC to kill Hc yeasts leads to the development of protective immunity, and that these functions are regulated by specific receptor-ligand interactions. The goal of this proposal is to determine how receptor-ligand interaction between Hc yeasts and macrophages and DC regulates pathogenesis and host defense. We have identified CD18 as the receptors on macrophages that recognize Hc yeasts, and the fibronectin receptor very late antigen 5 (VLA-5) as the receptor on DC that recognizes Hc yeasts. Most recently we identified heat shock protein 60 (hsp60) as the Hc ligand recognized by macrophage CD18. The major objectives of this proposal are: 1), to characterize Hc cyclophilin A as an adhesin for DC VLA-5; 2), to define the immunoregulatory role of cyclophilin A with respect to the interaction of Hc yeasts with DC and macrophages; and 3), to determine how the absence of cyclophilin influences the course of Hc infection in amurine model of pulmonary histoplasmosis, and if cyclophilin stimulates protective immunity. Knowledge gained from these studies will provide significant insight into the pathogenesis of histoplasmosis, host defense, and a basis for the development of novel vaccine strategies for the prevention of histoplasmosis.
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