This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toxoplasma gondii is a zoonotic human parasite with worldwide distribution. In addition to its classical association with fetal malformation (a leading cause of congenital neuropathy, affecting 1/1000 live births in the US) and abortion, toxoplasmosis also afflicts the growing ranks of immunocompromised individuals (cancer and transplant patients). Primary infection (acquired via ingestion of cysts in contam?inated water, soil, or under?cooked meat) leads to an initial systemic spread of tachyzoite parasites with mild to no symptoms, which mature into bradyzoite tissue cysts 1 week post-infection. In contrast to primary maternal infection which strongly affects the fetus, disease in the immunosuppressed patient population is primarily due to reactivation of dormant bradyzoite cysts residing in patient tissues and can lead to significant morbidity. Approximately 30% of the U.S. population is chronically infected with T. gondii, and harbor chemo- and immuno-resistant bradyzoite cysts within their tissues, particularly brain and muscle. Published studies have suggested that lifelong infection may produce psychological phenotypes in humans;however, there is no known treatment for the chronic bradyzoite stage of infection. Very recently, we have published a study of non-proprietary compounds active against intracellular Toxoplasma gondii tachyzoite growth;however, we have not established their mechanism of action. Moreover, the effect of these compounds on the bradyzoite cysts remains untested. Therefore, we propose to investigate the mechanism of action for these early lead anti-Toxoplasma compounds, and investigate the effect these compounds exert on bradyzoite cysts. We will investigator the following specific aims:
Specific Aim 1 : Predict the likely mechanism of action of early lead anti-Toxoplasma compounds.
Specific Aim 2 : Assess the killing efficacy of early lead compounds against Toxoplasma gondii bradyzoites.
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