Microneme Function in Toxoplasma

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DESCRIPTION (provided by the applicant): The obligate intracellular protozoan Toxoplasma gondii can cause lethal disease (toxoplasmosis) during pregnancy or immune dysfunction and debilitating ocular pathology in otherwise healthy people. Rapid cycles of parasite invasion produce the hallmark necrotic lesions seen during reactivated infection. Our long term goal is to understand adhesion and its role in parasite dissemination, cell entry, and tissue colonization. Recent findings indicate that the micronemal adhesive complex TgMIC2-M2AP is a key component of the motility and cell invasion machinery. However, it remains poorly understood how these proteins assemble into a viable complex or what role the complex plays during in vivo infection. Also, the specific contributions of other invasion proteins that function alongside TgMIC2-M2AP remain obscure. Based on observations in related parasites, our general hypothesis is that Toxoplasma microneme proteins contribute to tissue invasion and colonization during infection. Our specific aims are to 1) Define the domain interactions and sequence of events associated with assembly of the TgMIC2-M2AP complex; 2) Elucidate the role of the TgMIC2-M2AP complex in infection using newly derived knockout and knockdown strains; and 3) Assess the contributions of other novel invasion proteins identified in our recent proteomic screen to cell entry and infection. These studies will provide a deeper understanding of the molecular basis of Toxoplasma adhesion and its role in infection and pathogenesis. Because cell adhesion is an essential feature of the parasite, we anticipate these studies may lead to novel future opportunities to interrupt infection and potentially ameliorate disease.