Endothelial Cell Uptake of Infected Erythrocytes in Cerebral Malaria

脑型疟疾中感染红细胞的内皮细胞摄取

• 批准号: 9112857
• 负责人: Keith Burridge
• 金额: $ 22.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112857
• 关键词: Affect; Antimalarials; Apical; Apoptosis; Binding; Blood - brain barrier anatomy; Blood Vessels; Brain; CD36 gene; Carrier Proteins; Cell Communication; Cell Death; Cell Line; Cell membrane; Cerebral Malaria; Cerebrovascular system; Cerebrum; Clinical; Coma; Communicable Diseases; Disease; Endothelial Cells; Endothelium; Erythrocytes; Event; Functional disorder; Future; Goals; Grant; Health; Human; ICAM1 gene; Image Analysis; In Vitro; Infection; Inflammation; Inflammatory Response; Intercellular Junctions; Lead; Leukocytes; Link; Malaria; Mediating; Membrane Proteins; Modification; Molecular; Necrosis; Neurologic; Obstruction; Oxygen; Parasitemia; Parasites; Pathogenesis; Pathology; Pathway interactions; Peripheral; Permeability; Plasmodium falciparum; Play; Reporting; Role; Signal Pathway; Signal Transduction; Staging; Symptoms; TNF gene; Testing; Tight Junctions; Tissues; Up-Regulation; Work; activated protein C receptor; brain endothelial cell; burden of illness; improved; killings; malaria infection; migration; monolayer; mortality; novel; peripheral blood vessel; prevent; receptor; survival outcome; therapeutic development; uptake

 DESCRIPTION (provided by applicant): Malaria due to Plasmodium falciparum remains one of the largest global infectious disease burdens, infecting over 200 million and killing nearly 700,000 people annually. Of several possible disease manifestations, cerebral malaria has the worst survival outcomes. Cerebral malaria, characterized by coma and neurological deficits, ensues when parasitized red blood cells (pRBCs) sequester in the cerebral vasculature. Cytoadherence can contribute to disease by obstructing peripheral blood vessels, limiting oxygen delivery to tissue, and inducing significant inflammation. Cerebral pRBC sequestration is linked to breakdown of the blood brain barrier, yet the molecular mechanisms mediating vascular damage in cerebral malaria are poorly understood. The host inflammatory response plays a major role, but a more complete understanding of sequestration-related pathophysiology is necessary to develop adjunct therapies for cerebral malaria. Recent in vitro findings demonstrate that human brain endothelial cells (ECs) take up pRBCs via formation of an apical cup resembling endothelial protrusions known to mediate leukocyte transendothelial migration (TEM). ICAM1 binding in TEM activates signaling that induces cytoskeletal remodeling and junction opening to allow for migration either through or between ECs. Since pRBCs also bind ICAM1 and the cup- formation described in pRBC uptake resembles that associated with transcellular TEM, we hypothesize that pRBC cytoadherence can mistakenly induce uptake via TEM pathways and that this contributes to the pathology of cerebral malaria. Our aims seek: 1) to explore the relationship between cup formation and pRBC uptake by ECs, investigating the receptors involved and comparing different clinical isolates of P. falciparum for their ability to induce cup formation; and 2) to determine how pRBC-induced cups and uptake contribute to disruption of the EC barrier, whether this occurs by signaling pathways that open junctions or by inducing cell death. Our long term goal is to understand how pRBCs induce endothelial activation and blood brain barrier breakdown in order to improve therapeutic development. Not only is characterizing endothelial pRBC uptake in the context of leukocyte TEM pathways a novel idea, but exploring pRBC uptake has significant implications for understanding and controlling cerebral malaria pathology.

 描述（由适用提供）：由于恶性疟原虫而引起的疟疾仍然是全球最大的传染病伯恩伦斯之一，每年被感染了2亿多人，每年造成近70万人丧生。在几种可能的疾病表现中，脑疟疾的生存结果最差。脑疟疾以昏迷和神经系统缺陷为特征，当脑血管中寄生的红细胞（PRBC）隔离时，随之而来。细胞疗法可以通过阻塞外周血血管，将氧气递送到组织并诱导重大感染来导致疾病。脑PRBC固结与血脑屏障的分解有关，但是介导脑疟疾血管损伤的分子机制知之甚少。宿主炎症反应起着主要作用，但是对隔离相关的病理生理学的更全面了解对于开发脑疟疾的辅助疗法是必要的。最近的体外发现表明，人脑内皮细胞（EC）通过形成重新组合的内皮内皮蛋白来吸收PRBC，已知可介导白细胞跨内皮迁移（TEM）的内皮蛋白。 ICAM1在Temac Activates信号传导中结合，可诱导细胞骨架重塑和连接开口，以允许通过EC迁移或之间的EC迁移。由于PRBC还结合了ICAM1和PRBC摄取中所述的杯形，类似于与跨细胞TEM相关的杯子，因此我们假设PRBC细胞疗法可以通过TEM途径错误地诱导摄取摄取，这有助于大脑疟疾的病理学。我们的目标寻求：1）探索ECS杯形成与PRBC吸收之间的关系，研究所涉及的接收器，并比较恶性疟原虫的不同临床分离株，以影响其影响杯形成的能力； 2）为了确定PRBC诱导的杯子和吸收如何有助于EC屏障的破坏，无论是通过打开连接处还是通过诱发细胞死亡的信号通路来发生这种情况。我们的长期目标是了解PRBC如何诱导内皮激活和血脑屏障的崩溃，以改善热发育。不仅在白细胞途径的背景下表征内皮PRBC的吸收是一种新颖的想法，而且探索PRBC摄取对理解和控制脑疟疾病理学具有重要意义。