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Funcational Analysis of CD8T Cell Immune Control in Toxoplasma Gondii Infection


Toxoplasma gondii is an important opportunistic infection of AIDS patients. Improved strategies and approaches are urgently needed to more effectively prevent and treat recurrent infections in AIDS. Despite extensive knowledge of host immune response to T. gondii infection, no vaccine is yet approved for use in humans for this parasite or any other protozoan parasite causing opportunistic infection in AIDS.<P> Following an acute primary infection, a chronic life-long T. gondii infection is established in CNS/brain and this chronic infection is characterized by the persisting presence of cysts containing slowly replicating bradyzoite parasite forms. Reactivation of active infection due to rupture of brain cysts in chronic infection is the major mechanism causing difficult to treat and life-threatening Toxoplasmic encephalitis in AIDS. A major gap exists in our understanding of the antigen-specific immune factors that control acute infection and chronic infection. <P> Our preliminary data shows that CD8+ T cells control acute infection and prevent cyst rupture in chronic infection. CD8+ T cells and IFN-3 production are critical mediators of immune control in acute primary and chronic T. gondii infection.<P> We hypothesize that immune control of acute and chronic infection is highly dependent on antigen-specific CD8+ T cell populations that recognize specific parasite-derived epitopes presented to MHC class I during infection. This hypothesis will be tested by investigating the functional importance of defined CD8+ T cell epitopes in mediating control of acute and chronic infection in experiments using mutant virulent strains as well as mutant attenuated vaccine strains that lack known endogenous parasite-derived CD8+ T cell epitope(s). <P> The functional importance of defined CD8+ T cell epitopes in eliciting protective immunity to lethal acute infection will be determined, as well as the ability of a normally pre-established vaccine-induced immunity to protect against a virulent mutant strain lacking specific parasite-derived CD8+ T cell epitope(s). This innovative and exploratory study will functionally reveal whether any of the four recently identified and potentially immunodominant parasite-derived CD8+ T cell epitopes and their corresponding CD8+ T cell populations determine the immune control of acute and chronic T. gondii infection. <P> This project offers significant impact as it is relevant to the understanding of immune control of acute and chronic infection, which will allow future studies to focus on the most critical parasite antigens and their antigen-specific CD8+ T cell responses. This project is also is relevant for the improvement of vaccine design and to identify new interventions to address chronic infection in AIDS. <P> PUBLIC HEALTH RELEVANCE: This project is relevant to understanding immune control of acute and chronic infection in the AIDS opportunistic pathogen Toxoplasma gondii. No vaccine is currently available to prevent infection, and no treatment is available to eradicate chronic infection in infected individuals. By addressing fundamental and functional aspects of immune control in T. gondii infection in this project, we expect to reveal new information that can be directly applied to vaccine development to prevent infection, as well as to identify potential interventions to eliminate chronic infection in already infected people who are particularly at risk of serious recurrent infection(s).

Bzik, David
Dartmouth College
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