Pathogenesis of HRPII in Cerebral Malaria

项目总结/摘要 疟疾折磨着数亿人，每年造成60多万人死亡 这一年，大多数是撒哈拉以南非洲的儿童。恶性疟原虫引起 几乎所有的疟疾死亡。最可怕的恶性疟原虫并发症， 脑型疟疾，尽管进行了抗疟治疗，但往往是致命的。脑型疟疾 (CM)是一种脑血管疾病寄生红细胞（RBC）隔离 并可能导致微血管阻塞。虽然这 血管的机械堵塞被认为是导致疾病的原因， 功能障碍被认为起主要作用。病理学上， 观察到连接蛋白与血脑屏障渗漏有关。 近十年前，观察到恶性疟原虫感染的红细胞放置在 对体外内皮屏障的作用， 单层我们发现这种影响是由于寄生虫的输出- 产生富含组氨酸的蛋白质II（HRPII）。HRPII与内皮细胞结合 并触发炎性小体，导致内皮连接蛋白 再分配和屏障破坏。在体内，HRPII导致血脑 屏障渗透性，并导致死亡率增加的小鼠模型的脑 疟疾尚未回答的问题是：HRPII如何与内皮细胞结合 表面？HRPII如何触发炎性小体？我们能阻止 这种毒素是什么？ 为了解决这些问题，目标1将确定内皮HRPII受体， 炎性小体启动机制。既有候选基因又无偏见 方法将被尝试。目标2将侧重于确定治疗 改善脑型疟疾的策略。我们将测试现有的药物， 炎性体途径以及内皮屏障稳定药物， 我们对HRPII作用的小鼠试验。我们预计，拟议的研究将 对脑型疟疾的发病机制有很大的了解， 新疗法来减轻恶性疟疾的毁灭性并发症 感染.

Project Summary/Abstract Malaria afflicts several hundred million and kills more than 600,000 people each year, mostly children in Sub-Saharan Africa. Plasmodium falciparum causes nearly all the malaria deaths. The most dreaded P. falciparum complication, cerebral malaria, is often fatal despite antimalarial treatment. Cerebral malaria (CM) is a cerebrovascular disease. Parasitized red blood cells (RBCs) sequester in the small vessels and can cause microvascular obstruction. While this mechanical plugging of vessels is thought to contribute to disease, endothelial dysfunction is proposed to play a major role. Pathologically, redistribution of tight junction proteins is observed in association with blood-brain barrier leakage. Nearly a decade ago, it was observed that P. falciparum-infected RBCs placed on an in vitro endothelial barrier caused increased permeability across the monolayer. We have discovered that this effect is due to export of the parasite- produced protein histidine-rich protein II (HRPII). HRPII binds to endothelial cells and triggers the inflammasome, resulting in endothelium junctional protein redistribution and barrier disruption. In vivo, HRPII causes increased blood-brain barrier permeability and leads to increased mortality in murine models of cerebral malaria. Unanswered questions are: how does HRPII bind to the endothelial surface? How does HRPII trigger the inflammasome? Can we block the effects of this toxin pharmacologically? To address these questions, aim 1 will identify endothelial HRPII receptor and inflammasome initiation mechanism. Both candidate gene and unbiased approaches will be tried. Aim 2 will focus on identification of therapeutic strategies for amelioration of cerebral malaria. We will test existing drugs against the inflammasome pathway as well as endothelial barrier-stabilizing drugs, using our mouse assays for HRPII action. We anticipate that the proposed studies will yield great insight into the pathogenesis of cerebral malaria and will point the way to new therapies to mitigate the devastating complications of falciparum malaria infections.