Toxoplasma gondii is a serious pathogen of humans and livestock in the U.S.A. and world-wide. In addition to its well-known pathogenesis in the developing fetus, in recent years this protozoan parasite has increased its notoriety through the fatal disease it can cause in AIDS patients. Currently, there is no vaccine for Toxoplasma that is designed to impact human health. As well, the existing drugs are toxic and poorly tolerated in long-term treatment, as is necessary with AIDS patients. There is thus an urgent need for further research in these areas. Disease in AIDS patients is thought to largely result from the reactivation of a chronic infection that persists through the ability of the parasite to differentiate from the actively dividing tachyzoite stage to an encysted bradyzoite stage. In healthy people, the occasional rupture of these cysts is easily dealt with by the immune system but, upon becoming immuno-compromised, such releases result in the dissemination and uncontrolled growth of the virulent tachyzoite form. The resulting tissue destruction, particularly in the brain and lungs can lead to severe disease or even death. The goal of this proposal is to identify the genes involved in differentiation from tachyzoite to bradyzoite and then exploit our findings to engineer a strain that could form the basis for a vaccine in livestock, which represents a major source of human infection. Our approach to identifying the genes is to generate mutants defective in the tachyzoite to bradyzoite differentiation in vitro. The affected genes will be identified by complementation and characterized with regard to their role in the differentiation process. They will then be deleted and the resulting strains examined for their ability to infect and persist in animals. The result will be a strain that is self-limiting and non- transmissible since tachyzoites are not naturally infectious. This could form the appropriate genetic background for further alterations that attenuate virulence to create the ideal vaccine strain.
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