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.

项目摘要/摘要 疟疾折磨了数亿，每人杀死60万人 一年，主要是撒哈拉以南非洲的儿童。恶性疟原虫原因 几乎所有疟疾死亡。恶性疟原虫最恐惧的并发症， 尽管抗疟疾治疗，脑疟疾通常是致命的。脑疟疾 （CM）是一种脑血管疾病。寄生的红细胞（RBC）隔离 在小血管中，可能引起微血管阻塞。同时 据认为，船舶的机械堵塞会导致疾病，内皮 提议功能障碍发挥重要作用。从病理上，紧密的重新分布 与血脑屏障泄漏相关，观察到结蛋白。 大约十年前，人们观察到了恶性疟原虫感染的RBC 在体外内皮屏障上，导致渗透率提高 单层。我们发现这种效果是由于寄生虫的出口引起的 产生富含蛋白质的蛋白质蛋白II（HRPII）。 HRPII与内皮细胞结合 并触发炎症体，导致内皮连接蛋白 重新分布和障碍中断。在体内，HRPII导致血脑和 屏障渗透性，导致脑大脑模型的死亡率增加 疟疾。未解决的问题是：HRPII如何与内皮结合 表面？ HRPII如何触发炎性体？我们可以阻止 这种毒素在药理学上？ 为了解决这些问题，AIM 1将识别内皮HRPII受体和 炎性体的起始机制。候选基因和公正 将尝试方法。 AIM 2将专注于治疗的识别 改善脑疟疾的策略。我们将测试现有药物针对 使用炎性途径以及内皮屏障稳定药物，使用 我们的HRPII动作的鼠标测定法。我们预计拟议的研究将 对脑疟疾的发病机理产生深刻的了解，并将指向道路 为了减轻恶性疟疾的破坏性并发症，以减轻新疗法 感染。