Initial Events in Human Ocular Toxoplasmosis

描述（由申请人提供）：眼部弓形虫病是由弓形虫寄生虫感染引起的一种眼部炎症性疾病。仅在美国，这种情况估计影响超过125万人。在其他方面健康的成年人中，他们构成了受眼弓形体病影响的最大群体，永久性视力损害是一种常见的结果。在免疫功能低下的个体和先天感染的儿童中观察到特别具有侵袭性的疾病。抗菌治疗可以抑制寄生虫的生长，但副作用很常见，而且没有药物可以根除眼组织中的寄生虫。这项工作的总体目标是了解在人眼中建立眼弓形虫病的基本机制。虽然在弓形虫生物学领域有相当大的进展，但有关人类眼部感染机制的基本问题仍未得到解答。重要的是，目前尚不清楚弓形虫是如何从血液中进入人眼的。此外，目前还不清楚人眼中的哪些细胞群更容易被寄生虫感染。最后，没有关于寄生虫基因型对这些事件影响的信息。本项目基于不同菌株的寄生虫与眼部细胞和组织的相互作用不同的假设。弓形虫或被寄生的单核细胞结合和迁移人眼部血管内皮的能力将分别通过体外和离体结合试验和跨井迁移试验进行评估。将研究游离寄生虫在新鲜人眼组织内的运动，并利用分离的视网膜培养物建立不同眼细胞对感染的敏感性。将比较选定的弓形虫菌株，以确定寄生虫遗传学对眼弓形虫病发病时人眼中发生的事件的影响。公共卫生相关性：眼弓形虫病是一种威胁视力的寄生虫性眼部感染，在美国很常见。这种病没有治疗方法。这项工作将描述感染开始时眼睛中发生的事件，这是朝着开发更有效的治疗方法迈出的重要的第一步。

DESCRIPTION (provided by applicant): Ocular toxoplasmosis is an inflammatory eye disease caused by infection with the parasite, Toxoplasma gondii. In the US alone, this condition is estimated to affect over 1.25 million individuals. In otherwise healthy adults, who constitute the largest group affected by ocular toxoplasmosis, permanent visual impairment is a common outcome. Particularly aggressive disease is observed in immunocompromised individuals and congenitally infected children. Antimicrobial treatments may suppress growth of the parasite, but side effects are common, and no drug eradicates encysted parasites from the ocular tissues. The overall objective of this work is to understand the basic mechanisms operating in the human eye during establishment of ocular toxoplasmosis. Although there have considerable advances in the field of T. gondii biology, basic questions relating to the mechanisms of human ocular infection remain unanswered. Importantly, it is not known how T. gondii gains access to the human eye from the blood stream. In addition, it is unclear which cell populations within the human eye are preferentially infected by the parasite. Finally, there is no information regarding the impact of parasite genotype on these events. This project is based on the hypothesis that parasites of different strains interact differently with the ocular cells and tissues. The ability of T. gondii or parasitized monocytes to bind to and migrate across human ocular vascular endothelium will be evaluated using in vitro and ex vivo binding assays, and a transwell migration assay, respectively. Movement of free parasites within fresh human ocular tissue will be investigated, and the susceptibility of different ocular cells to infection will be established using dissociated retinal cultures. Selected T. gondii strains will be compared to determine the influence of parasite genetics on the events that occur in the human eye at the onset of ocular toxoplasmosis. PUBLIC HEALTH RELEVANCE: Ocular toxoplasmosis is a vision-threatening parasitic eye infection that is common in the US. No treatment cures the disease. This work will characterize the events occuring in the eye at the onset of the infection, which is an important first step toward the development of more effective treatments for patients with the condition.