IFN-gamma production by microglia for prevention of toxoplasmic encephalitis

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DESCRIPTION (provided by applicant): Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE, it is important to understand the immunopathogenesis of the disease. The murine models of TE that we developed provide an excellent opportunity to critically analyze the mechanisms of host defense in the brain. It is well documented that T cells recruited into the brain are an essential source of IFN-3 for prevention of TE. However, it is not known how the host defense functions during the early stage of reactivation of infection before large numbers of T cells enter the brain. This early defense system could be crucial for limiting tachyzoite growth and initiating T cell immunity to prevent TE. We recently found that microglia, which are resident macrophages in the brain parenchyma, produce IFN-3 during the early stage of reactivation. Our studies also suggest that production of IFN-3 by brain-specific cells, in addition to T cells, is required for prevention of TE. Therefore, IFN-3 production by microglia appears to be a novel early defense mechanism essential for prevention of the disease. The specific aims in this proposal are designed to define the role of IFN-3 produced by microglia in inhibition of tachyzoites growth, induction of T cell immunity, and prevention of TE. In the first aim, we will examine the inhibitory effects of IFN-3 produced by microglia on tachyzoite proliferation in the brain after reactivation of infection using mice that have IFN-3 production only by microglia. The second aim is to determine if IFN-3 production by microglia induces expression of mediators that recruit T cells into the brain. We will examine whether IFN-3 production by microglia induces expression of chemokines in brain cells and adhesion molecules on cerebrovascular endothelial cells. We will then use in vivo T cell migration assays to determine whether IFN-3 production by microglia facilitates infiltration of immune T cells into the brain. The third aim is to determine if IFN-3 production by microglia induces expression of MHC molecules for activation of T cells in the brain. In the fourth aim, we will determine the requirement of IFN-3 production by microglia and T cells for prevention of TE. For this purpose, we will purify immune T cells from infected wild-type or IFN-3-deficient mice and transfer these T cells into infected mice that express IFN-3 only by microglia or lack expression of this cytokine. Host mice will be followed for development of TE. We will also examine the role of IFN-3-dependent mediators of T cell recruitment determined in Specific Aim 2 for prevention of TE. The studies in these four specific aims will provide novel and crucial information that allows us to understand how IFN-3-production by microglia enables the host defense system in the brain to prevent TE. PUBLIC HEALTH RELEVANCE Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). The proposed studies are to analyze how brain cells (microglia) inhibit parasite growth and induce the immune responses to prevent TE. This information will contribute to better understanding of the immunopathogenesis of TE and to improved prevention and management of the disease.