Pathogenesis of HRPII in Cerebral Malaria

HRPII 在脑型疟疾中的发病机制

• 批准号: 9913445
• 负责人: Daniel E. Goldberg
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-12 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913445
• 关键词: Address; Africa South of the Sahara; Agonist; Angiotensin Receptor; Antibodies; Antimalarials; Binding; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CASP1 gene; Candidate Disease Gene; Cerebral Malaria; Cerebrovascular Disorders; Cerebrum; Cessation of life; Child; Co-Immunoprecipitations; Coma; Complication; Disease; Drug usage; Endothelial Cells; Endothelium; Erythrocytes; Extravasation; Falciparum Malaria; Fluorescein; Human; Immunohistochemistry; In Vitro; Infection; Inflammasome; Interferons; Interleukin-1 Receptors; Malaria; Mass Spectrum Analysis; Mechanics; Mediating; Mus; Neurologic; Obstruction; Parasites; Pathogenesis; Pathologic; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Plasmodium falciparum; Play; Proteins; Resistance; Role; Severity of illness; Signal Pathway; Sphingosine-1-Phosphate Receptor; Streptavidin; Surface; Survivors; Testing; Therapeutic; Tight Junctions; Toxin; alpha Toxin; blood-brain barrier permeabilization; endothelial dysfunction; histidine-rich proteins; in vivo; insight; knock-down; malaria infection; monolayer; mortality; mouse model; novel therapeutics; prevent; receptor; response; small hairpin RNA

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.

项目概要/摘要 疟疾困扰着数亿人并导致超过 60 万人死亡 年，主要是撒哈拉以南非洲地区的儿童。恶性疟原虫的病因 几乎所有因疟疾死亡的人。最可怕的恶性疟原虫并发症， 尽管接受抗疟治疗，脑型疟疾仍常常致命。脑型疟疾 (CM)是一种脑血管疾病。寄生红细胞 (RBC) 隔离 存在于小血管中，可引起微血管阻塞。虽然这 血管的机械堵塞被认为会导致疾病、内皮细胞疾病 功能障碍被认为发挥着重要作用。从病理学上讲，紧绷的重新分布 观察到连接蛋白与血脑屏障渗漏有关。 大约十年前，人们观察到感染恶性疟原虫的红细胞被放置在 对体外内皮屏障的作用导致跨过内皮屏障的通透性增加 单层。我们发现这种效应是由于寄生虫的输出造成的—— 产生富含组氨酸的蛋白 II (HRPII)。 HRPII 与内皮细胞结合 并触发炎症小体，产生内皮连接蛋白 重新分配和障碍破坏。在体内，HRPII 会导致血脑屏障增加 屏障通透性并导致小鼠脑模型的死亡率增加 疟疾。悬而未决的问题是：HRPII 如何与内皮细胞结合？ 表面？ HRPII 如何触发炎症小体？我们能否阻止其影响 这种毒素有药理作用吗？ 为了解决这些问题，目标 1 将鉴定内皮 HRPII 受体并 炎症小体启动机制。候选基因和无偏基因 将尝试各种方法。目标 2 将侧重于确定治疗方法 改善脑型疟疾的策略。我们将测试现有药物 炎症体途径以及内皮屏障稳定药物，使用 我们对 HRPII 作用的小鼠进行了检测。我们预计拟议的研究将 对脑型疟疾的发病机制有深入的了解，并将指明方向 减轻恶性疟疾破坏性并发症的新疗法 感染。