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刚地弓形虫（Toxoplasma gondii）通过血脑屏障（BBB）等生物屏障到达中枢神经系统。在免疫功能低下的患者（艾滋病患者和移植患者）中，潜伏感染的重新激活导致严重的病理。目前尚不清楚弓形虫是作为游离的细胞外寄生虫传播，还是存在于受感染的白细胞中，后者是可以跨越许多生物屏障的允许宿主（特洛伊木马理论）。GR-1+单核细胞在感染早期被招募到感染部位，产生包括IL-12在内的促炎细胞因子，并有助于控制寄生虫的复制。然而，这些细胞在血脑屏障的转运和潜伏感染的再激活中的作用尚不清楚。在这项研究中，我将探讨弓形虫在血脑屏障中的传播和迁移机制。利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通过细胞外和/或细胞内途径在大脑中建立自己。此外，还将探讨紧密连接蛋白和粘附分子在转运过程中的作用。最后，我将利用小鼠模型研究GR-1+单核细胞在感染急性期和再激活后控制寄生虫复制中的重要性。

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.