Molecular immunopathogenesis of cerebral toxoplasmosis

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DESCRIPTION (Provided by the applicant): Toxoplasmic encephalitis (TE) is a life-threatening disease in immunocompromised patients such as those with AIDS. The immunopathogenesis of TE remains to be defined. We have identified three factors to be critical for determining the host resistance to this disease. These are IFN-gamma-mediated immune response, the genetic background of the host and the strain (antigens) of T. gondii. It appears that the genetic background of the hostand the strain (antigens) of T. gondii affect the IFN-gamma-mediated immune response, thereby contribute to determining the host resistance. Thus, for obtaining understanding of the molecular basis of host resistance to TE, I propose to define the mechanisms how IFN-gamma-mediated immune response is operated in the brain and how the genetic background of the host and the strain (antigens) of T. gondii affect the immune response. To accomplish this long-term specific aim, I will address three main questions in this proposal. My recent preliminary studies demonstrated that infected athymic nude and SCID mice, which lack T cells, had high levels of IFN-gamma expression in their brains. Another series of preliminary studies using a transfer of immune T cells demonstrated that such IFN-gamma expression by the non-T cell(s) is required for transferred immune T cells to demonstrate their protective activity in the brain to prevent TE. Thus, the first specific aim is to identify the non-T cell(s) which produces IFN-gamma in the brain and to analyze the role and function of T cells in their collaboration with the non-T cell(s) for prevention of TE. The second specific aim is to analyze the mechanism of T cell entry into the brain in infected host. T cells need to enter the brain to exert their protective activity. My preliminary studies suggested an important role for IFN-gamma, in regulating T cell trafficking into the brain of infected mice. Thus, I propose to analyze the role for IFN-gamma, in regulation of expression of adhesion molecules involved in cell trafficking on cerebral vessels and T cells. Under this specific aim, I also propose to analyze the role of IFN-gamma and adhesion molecules on the T cell entry into the brain. The third specific aim to address the effects of host genes on the protective immune response to TE. Since my preliminary studies revealed an importance of Vbeta8-bearing T cells in genetic resistance of BALB/c mice to TE, I propose to analyze the mechanism of the protective activity of this T cell population in their resistance. I also propose to analyze T. gondii antigen(s) which stimulate Vbeta8-bearing T cells.