IMMUNE REGULATION IN TOXOPLASMOSIS AND OTHER OPPORTUNISTIC INFECTIONS

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The overall aim of this project is to analyze the immune response to Toxoplasma gondii and other opportunistic infections in order to define which cellular immune components and parasite target antigens are involved int he control of infection and its breakdown in immunocompromised hosts. An additional goal is to examine possible effects of these pathogens on HIV-1 infection. Progress was made this year in the following areas: 1) Characterization of host resistance mechanisms in a murine model of Mycobacterium avium infection. A mouse model of M. avium was established and the immunologic basis of resistance to this opportunistic pathogen in the early and late stages of infection characterized. 2) Induction of HIV-1 proviral expression by opportunistic pathogens in a murine transgenic mouse model. T. gondii and M. avium were shown to induce HIV-1 proviral RNA expression in a murine transgenic mouse model and to stimulate the production of infectious viral particles in vitro. 3) Characterization of T. gondii molecules responsible for TNF-gamma and IL-12 induction. A lipid-like molecule was partially purified from T. gondii extracts which has potent TNF-alpha-inducing activity in macrophages. The same material triggered IL-12 production when a macrophage-priming signal was included. 4) Host resistance to T. gondii infection in gene knockout mice. Mechanisms controlling acute and chronic infection with T. gondii were examined in a variety of knockout mice with defects in cellular immune function. New information concerning the role of inducible NO synthase, perforin-dependent cytolysis and CD4+ NK1.1+ cells in host resistance was obtained.