Toxoplasma gondii is a ubiquitous Apicomplexan protozoan parasite of mammals and birds, which is responsible for several important clinical syndromes in humans. The predilection of this parasite for the central nervous system (CNS) causing behavioral disorders and especially, fatal necrotizing encephalitis constitutes its major threat to patients with WV infection. CNS toxoplasmosis ranks among the ten most commonly occurring opportunistic infections in AIDS patients, and may well be a greater direct cause of morbidity and mortality than other more common opportunistic infections. If acquired during pregnancy infection can result in the syndrome of congenital toxoplasmosis with attendant encephalitis, mental retardation, and chorioretinitis. In both conditions, reactivation of the latent encysted state of the organism (bradyzoite) to the active replicative form (tachyzoite) is associated with progression of disease and is directly implicated in the pathology that attends this infection. Despite major advances in our understanding of the cell biology of T. gondii as well as our ability to manipulate this parasite in vitro, very little is known about the developmental pathways and control mechanisms in the transition of tachyzoites to bradyzoites. Stress conditions are associated with the induction of bradyzoite development and in the last granting period we identified several beat shock proteins (lisps) associated with this differentiation event. BAG 1, a small heat shock protein (sxnHsp), is induced early during bradyzoite differentiation. This smHsp was cloned and a knockout constructed. The BAG1 knockout formed fewer cysts in vivo; suggesting that BAG1 was associated with the ability of T. gondif to form cysts. In addition, we identified a glycoprotein, CST1, that is also induced early during bradyzoite development. We now plan to focus our studies on the differentiation or developmental biology of T. gondii and define those factors that are involved in the interconversion of the active or acute stage to the latent or chronic stage of this disease. Thus, this proposal will entail the characterization of a unique early bradyzoite antigen CST1, definition of the function(s) of BAG1 (a smHsp) and the characterization of the stress response in T. gondil. Each of these specific aims will fUrther our understanding of the early events in bradyzoite differentiation leading to chronic (latent) toxoplasmosis. Therapeutic modalities aimed at interdicting bradyzoite formation should eradicate this infection in the infected host, thereby eliminating bradyzoite reactivation which is the key element in the development of CNS toxoplasmosis in AIDS.
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