The long term objective is to utilize-a Cryptococcus neoformans infection model in mice to study the pathogenesis and possible methods of control of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS). In the majority of patients with AIDS, the respiratory tract is the probable portal of entry for the opportunistic infectious agent and/or pulmonary disease is the most devastating manifestation of the infection. In the murine model the organism is inoculated via the trachea and first establishes an infection in the lung. Using a virulent cryptococcal strain, the organism disseminates from the lung and the animal dies of a fatal meningitis. As in patients with AIDS, in T cell deficient mice the infection follows a more aggressive course. Studies are designed to examine both local pulmonary and extrapulmonary defenses that are crucial in controlling the infection with particular emphasis on nonspecific effector mechanisms.
Specific aims are: (1) The relative importance of macrophages, NK cells and neutrophils in resistance to C. neoformans in nonimmune mice will be determined. Growth inhibition of C. neoformans in vitro by isolated cells from lung, spleen and peritoneal exudates (as representative of cells that can be recruited to infected organs) will be performed. The effect of the immunomodulators Corynebacterium parvum, Isoprinosine, recombinant interferon-gamma (rIFN-gamma) and recombinant Interleukin-2 (rIL- 2) on activation of these cells in vitro will be assessed. In addition, cryptococcal clearance will be studied in vivo under conditions where these effector cells are depleted or their activity is enhanced. (2) The capacity of murine lung to develop T cell dependent immunity against C. neoformans will be investigated by isolating immunologically relevant cells (T lymphocytes and antigen presenting cells) from enzymatically digested lung of normal and C. neoformans-infected animals and testing their function in vitro. (3) It will be determined whether the increased survival induced by rIL-2 in normal mice given a lethal dose of C. neoformans is dependent on NK cells or T cells by depleting rIL-2-treated mice of these cells using monoclonal antibodies. (4) It will be determined which effector mechanisms are defective in T cell deficient mice to explain their decreased resistance to C. neoformans. Then it will be determined whether T cell deficient mice can be protected from infection using C. parvum, Isoprinosine, rIFN-gamma and rIL-2.
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