Blood-brain barrier traversal by African trypanosomes

描述：（由申请人提供）：睡眠的神经症状 布氏冈比亚锥虫和T B引起人类疾病。罗得西亚群岛 由于锥虫对中枢神经系统的渗透。 然而，非洲锥虫如何穿过血脑屏障（BBB）仍然是一个问题。 未解决的问题。利用体外人脑血脑屏障系统， 微血管细胞（BMEC），我们已经启动了旨在破译 非洲锥虫穿越血脑屏障的机制。初步研究 表明人类感染性T. B.冈比亚血吸虫分离株 与动物感染性T. B. 427. casino寄生虫似乎与细胞间连接处结合， BMEC。同样能动的原轮形式不结合或也不交叉， 屏障更重要的是，血脑屏障紧密连接保持完整， 已经在体内描述过了。抑制寄生虫BBI3 蛋白酶抑制剂的交叉表明寄生虫蛋白酶在 血脑屏障渗透。我们的体外人血脑屏障模型将是一个重要的工具， 了解非洲锥虫如何穿过血脑屏障的总体目标 这项研究将检查非洲锥虫的体外潜力， 穿过宿主的血脑屏障， 机制。我们将描述相互作用的动力学， 布氏锥虫穿越在体外血脑屏障模型中。我们将 识别屏障的穿越模式;例如，旁细胞或 跨细胞以及检查寄生虫的潜在机制 BMEC的互动。从拟议的研究中获得的结果将是一个 这是我们了解非洲锥虫最初事件的重要一步 侵入大脑有了这些知识，我们将能够更好地 设计治疗方法，阻止寄生虫进入大脑， 防止许多痛苦的神经症状，最终导致 死亡

DESCRIPTION: (provided by the applicant): The neurological symptoms of sleeping sickness in man caused by Trypanosoma brucei gambiense and T b. rhodesiense are attributed to the penetration of the central nervous system by trypanosomes. Yet, how African trypanosomes cross the blood-brain barrier (BBB) remains an unresolved issue. Using an in vitro BBB system constructed of human brain microvascular cells (BMEC) we have initiated studies aimed at deciphering the mechanisms used by African trypanosomes to cross the BBB. Preliminary studies show that a human infective T. b. gambiense bloodstream form parasite isolate crossed the in vitro BBB model more efficiently than animal infective T. b. brucei 427. The parasites appeared to bind to intercellular junctions between BMEC. Equally motile procyclic forms do not bind or nor do they cross the barrier. More importantly, the BBB tight junctions remain intact, a finding that has been previously described in vivo. Inhibition of parasite BBI3 crossing by protease inhibitors suggests that parasite proteases play a role in BBB penetration. Our in Vitro model of the human BBB will be an important tool for understanding how African trypanosomes cross the BBB. The overall aims of this study will be to examine the in vitro potential of African trypanosomes to transverse the host blood-brain barrier and to dissect the underlying mechanism(s). We will characterize the kinetics of the interaction and traversal of Trypanosoma brucei spp. across an in vitro model of BBB. We will identify the mode of traversal of the barrier; e.g. paracellular or transcellular as well as examine the underlying mechanism(s) of the parasite and BMEC interactions. The results obtained from the proposed study will be a major step in our understanding of the initial events of African trypanosome invasion into the brain. Armed with this knowledge we will be better able to design therapies that will stop the parasites from entering the brain and prevent many of the agonizing neurological symptoms, which eventually lead to death.