Reactivation of chronic infection with Toxoplasma gondii in the brains of immunocompromised individuals results in development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE, it is important to understand the immunopathogenesis of the disease. Epidemiological studies showed significantly higher incidence of TE in female AIDS patients than male patients. Our previous studies in ADIS patients revealed the presence of a susceptibility marker gene to development of TE within the MHC complex, suggesting that the pathogenic immune responses predisposing the patients to reactivation of T. gondii infection are involved in the pathogenesis of TE. Consistent with the observation in AIDS patients, our preliminary studies uncovered that female mice are more susceptible to reactivation of cerebral T. gondii infection than males. However, the mechanisms of the pathogenic immune responses that predispose females to developing TE are unknown. In this regard, our preliminary studies suggested that IL-10 overly produced by innate immune cells in the brain of female mice suppresses the protective innate immune responses and skews cerebral T cell responses from the protective Th1-type to suppressive IL-10-dominant profile to facilitate reactivation of T. gondii infection. Thus, the goal of this project is to elucidate the crucial pathogenic roles of gender-dependent production of IL-10 by cerebral innate immune cells to down-regulate both protective innate and T cell-mediated immunity in the brain and increase susceptibility to TE. In the first aim, we will determine the pathogenic activities of IL-10 produced by each of brain-resident and infiltrating blood-derived innate immune cell populations on the protective innate immunity in the brain to facilitate reactivation of T. gondii infection in a gender-dependent manner. We will infect male and female SCID mice with depletion of IL-10 production in the different innate cell populations in the brain and determine the effects of the innate IL-10 depletion on cerebral expression of IL-12, IFN-? and IFN-?-mediated effector molecules, and tachyzoite growth during reactivation of the infection. We will also determine the identity of the major producer of the pathogenic innate IL-10 in the brain during reactivation of the infection.
The second aim i s to determine whether the gender-dependent cerebral innate IL-10 production alters T cell recruitment and/or development in the brain and skews T cell cytokine production from IFN-?- to IL-10-dominant profile to facilitate reactivation of T. gondii infection. We will transfer immune T cells to the infected SCID mice with depletion of IL-10 in the different innate cell populations described in Aim 1, and determine changes in numbers of sub-populations of CD4+ and CD8+ T cells that produce either IFN-? or IL-10 or both in their brains, expression of IFN-?-mediated protective effector molecules, and cerebral tachyzoite growth during the course of the infection. These studies will generate the novel and critical information that allow us to begin understanding the mechanisms of the pathogenic immunity that promotes reactivation of cerebral T. gondii infection in a gender-dependent manner.
Reactivation of chronic infection with Toxoplasma gondii in the brain causes life- threatening toxoplasmic encephalitis (TE) in immunocompromised individuals. The proposed studies are aimed to uncover the pathogenic roles of gender-dependent production of IL-10 by cerebral innate cells to increase susceptibility to development of TE. These studies will provide the cutting-edge information that dramatically improves our understanding of the regulatory mechanisms of host resistance against TE and assists in developing a novel method(s) to improve prevention and treatment of TE by suppressing the innate IL-10-mediated pathogenic mechanisms.
