Role of GR-1+ monocytes in dissemination and invasion of the brain by T. gondii, and defense against toxoplasmosis

细胞内原生动物寄生虫弓形虫（Toxoplasma gondii）穿过生物屏障，如血脑屏障（BBB）到达CNS。在免疫功能低下的患者（艾滋病和移植患者）中，潜伏感染的重新激活导致严重的病理学。目前尚不清楚弓形虫是否作为游离的细胞外寄生虫传播，或者是否存在于受感染的白细胞内，白细胞是可以跨越许多生物屏障的容许宿主（特洛伊木马理论）。GR-1+单核细胞在感染的早期阶段被募集到感染部位，产生促炎细胞因子，包括IL-12，并有助于控制寄生虫复制。然而，这些细胞在穿越血脑屏障和重新激活潜伏感染中的作用尚不清楚。本研究将探讨T.弓形虫在血脑屏障中的传播和迁移。使用血脑屏障的体外共培养模型以及体内研究，目的是确定弓形虫是否使用细胞外和/或细胞内途径在脑中建立自身。此外，紧密连接蛋白和粘附分子在迁移过程中的作用也将被探讨。最后，我将研究GR-1+单核细胞在控制寄生虫复制的重要性，在感染的急性期和重新激活后，使用小鼠模型。

The intracellular protozoan parasite Toxoplasma gondii traverses biological barriers such as the blood-brain-barrier (BBB) to reach the CNS. In immunocompromised patients (AIDS- and transplant patients), reactivation of the latent infection results in severe pathology. It is unknown whether Toxoplasma disseminates as free, extracellular parasites or if it resides inside infected leukocytes, which are permissive hosts that can cross many biological barriers (Trojan horse theory). GR-1+ monocytes are recruited to the site of infection during the early stage of infection, produce pro-inflammatory cytokines including IL-12, and contribute to control of parasite replication. However, the role of these cells in transmigration across the BBB and in reactivation of latent infection is unknown. In this study, I will investigate the mechanism(s) of T. gondii dissemination and transmigration across the BBB. Using an in-vitro co-culture model of the BBB as well as in-vivo studies it is the aim to determine whether Toxoplasma uses extracellular and/or intracellular pathways to establish itself in the brain. In addition the role of tight junction proteins and adhesion molecules in the process of transmigration will be explored. Finally, I will investigate the importance of GR-1+ monocytes in the control of parasite replication in the acute phase of infection and after reactivation, using the murine model.