Heparan sulfate in T.gondii attachment and invasion

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DESCRIPTION (provided by applicant): Toxoplasma gondii is a wide-spread intracellular parasite infecting humans and animals. The amazing ability of Toxoplasma to infect almost every mammalian has led to the hypothesis that it recognizes heparan sulfate, a surface glyconjugate found on a wide variety of cells. To address this hypothesis, we propose a set of studies to addresses the role of heparan sulfate in Toxoplasma attachment to endothelium. In Aim 1, we propose to examine T gondii attachment to mutant and siRNA gene silenced CHO cells in HS biosynthesis under conditions that mimic blood flow as compared to static conditions. Further, we will utilize heparin derivatives as potential therapeutic agents to blockattachment of these parasites. Toxoplasma can cause disease in humans is by crossing the blood brain barrier. Thus, Aim 2 will examine the role of HS in endothelial cell lines and bi-layersystems that mimic the blood brain barrier. The goal of this aim is to establish a role for HS in Toxoplasma attachment to endothelial cell tissues. We will utilize Cre-loxP recombinant systems to create endothelial cell knockout mice in HS biosynthesis, which can be tested for Toxoplasma tissue dissemintion. Further, these tissues can be removed and assayed for T gondii attachment ex vivo. The results of this study could lead to therapeutic strategies for treating not only Toxoplasmosis, hut a wide variety of parasitemias and other infections that utilize heparan sulfate for entry into mammalian cells.