Toxoplasmosis, caused by the obligate intracellular parasite, Toxoplasma gondii, is a major opportunistic infection in patients with AIDS. More than one third of all AIDS patients will suffer from central nervous infection with T. gondii during the course of illness. The incidence of congenital toxoplasma infection approaches 100% in children of mothers seropositive for both HIV and T. gondii. Previous studies in our laboratory and others suggest that T. gondii is able to suppress the immune system in the normal experimental host. However, the immune cells responsible for this, and the mechanism of immunosuppression remains unclear. In this FIRST Award project, I will investigate those parameters of immunosuppression in the experimental mouse model.
My first aim will be to develop an immunosuppressive experimental model of T. gondii infection. The cells responsible for this immune modulation will be identified and their phenotype characterized. These immune cells will then be used in experiments to ascertain whether the suppression can be adoptively transferred into naive mice. Another major aim will be to further understand the mechanism of this immunosuppressive response. In particular, analysis for the expression of specific cytokines known to suppress the immune system win be performed. This includes such cytokines as TGF-beta, IL-10 and macrophage deactivating factor (MDF). Once the cell type and mechanism of immunosuppression are better understood, I will develop and in vitro line or clone of T cells that are responsible for this immunosuppression. These cells can be analyzed for their genetic character as well as their ability to adoptively transfer immunosuppression. The last aim of this proposal will be to determine if a murine acquired immunodeficiency model (MAIDS) for experimental T. gondii infection can be established. Using this model of AIDS, I will try to identify the parasite antigens as well as the cytokine products of immunosuppressive T cells responsible for the accelerated toxoplasma infection in these animals. In particular, the role of CD8+ T cells will be evaluated based on previous observations suggesting the importance of this subset in protection against this obligate intracellular microbe. These studies will enable us to clarify the role of T. gondii mediated immunosuppression in down regulating the already damaged immune system in AIDS patients.
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