Initial Events in Human Ocular Toxoplasmosis

描述（由申请人提供）：眼弓形虫病是一种由寄生虫弓形虫感染引起的炎症性眼病。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，他们构成了受眼部弓形虫病影响的最大群体，永久性视力障碍是常见的结果。在免疫功能低下的个体和先天性感染的儿童中观察到特别侵袭性的疾病。抗微生物治疗可以抑制寄生虫的生长，但副作用很常见，并且没有药物可以从眼组织中根除包囊寄生虫。这项工作的总体目标是了解眼弓形虫病建立过程中在人眼中运作的基本机制。虽然T.在弓形虫生物学方面，与人类眼部感染机制有关的基本问题仍然没有答案。重要的是，它是不知道如何T。弓形虫通过血流进入人眼。此外，目前还不清楚人类眼睛内的哪些细胞群优先被寄生虫感染。最后，没有关于寄生虫基因型对这些事件的影响的信息。该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。T.将分别使用体外和离体结合测定和transwell迁移测定来评价弓形虫或寄生的单核细胞与人眼血管内皮的结合和迁移穿过人眼血管内皮。将研究新鲜人眼组织中游离寄生虫的运动，并使用分离的视网膜培养物确定不同眼细胞对感染的易感性。选择T.将比较弓形虫菌株以确定寄生虫遗传学对眼弓形虫病发作时在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性眼部感染，在美国很常见。没有治疗方法能治愈这种疾病。这项工作将描述感染开始时眼睛中发生的事件，这是为患者开发更有效治疗方法的重要第一步。

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.