Pathogenesis of HRPII in Cerebral Malaria

项目摘要/摘要 疟疾困扰着数亿人，每个人死于60多万人 去年，主要是撒哈拉以南非洲的儿童。恶性疟原虫致病原因 几乎所有死于疟疾的人。最可怕的恶性疟原虫并发症， 尽管接受了抗疟疾治疗，但脑型疟疾往往是致命的。脑型疟疾 (厘米)是一种脑血管疾病。寄生红细胞(RBCs)隔离器 在小血管中并可引起微血管阻塞。虽然这件事 机械堵塞血管被认为是导致血管内皮细胞疾病的原因之一 功能障碍被认为是起主要作用的。病理上，致密的重新分布 观察到连接蛋白与血脑屏障渗漏有关。 近十年前，观察到感染恶性疟原虫的红细胞将 体外血管内皮细胞屏障导致血管通透性增加 单层。我们发现，这种效应是由于寄生虫的出口- 产生富含组氨酸的蛋白II(HRPII)。HRPII与血管内皮细胞结合 并触发炎症小体，产生内皮结合蛋白 再分配和障碍破坏。在体内，HRPII导致血脑增加 屏障通透性并导致小鼠脑损伤模型死亡率增加 疟疾。悬而未决的问题是：HRPII如何与内皮细胞结合 浮出水面？HRPII是如何触发炎症小体的？我们能阻止 这种毒素是药理上的吗？ 为了解决这些问题，目标1将识别内皮HRPII受体和 炎性小体启动机制。既有候选基因又没有偏见 将尝试各种方法。目标2将专注于确定治疗方法 改善脑型疟疾的策略。我们将对现有的药物进行测试 炎症体途径以及内皮屏障稳定药物，使用 我们的小鼠检测HRPII的作用。我们预期拟议的研究将会 对脑型疟疾的发病机制有很大的洞察力，并将指明方向 以减少恶性疟疾的破坏性并发症的新疗法 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.