Endothelial Cell Uptake of Infected Erythrocytes in Cerebral Malaria

 描述（由申请人提供）：由恶性疟原虫引起的疟疾仍然是全球最大的传染病负担之一，每年感染2亿多人，造成近70万人死亡。在几种可能的疾病表现中，脑型疟疾的生存结果最差。以昏迷和神经缺陷为特征的脑型疟疾，当寄生红细胞（pRBC）隔离在脑血管系统中时发病。细胞粘附可通过阻塞外周血管、限制向组织的氧气输送和诱导显著炎症而促成疾病。脑pRBC隔离与血脑屏障的破坏有关，但对脑型疟疾中介导血管损伤的分子机制知之甚少。宿主的炎症反应起着重要的作用，但更完整地了解隔离相关的病理生理学是必要的，以开发脑型疟疾的辅助治疗。 最近的体外研究结果表明，人脑内皮细胞（EC）通过形成类似于已知介导白细胞跨内皮迁移（TEM）的内皮突起的顶杯来摄取pRBC。ICAM 1在TEM中的结合激活了诱导细胞骨架重塑和连接开放的信号传导，以允许通过EC或在EC之间迁移。由于pRBC也结合ICAM 1，并且在pRBC摄取中描述的杯状形成类似于与跨细胞TEM相关的杯状形成，我们假设pRBC细胞粘附可以错误地诱导通过TEM途径的摄取，并且这有助于脑型疟疾的病理学。我们的目标是：1）探索杯形成与EC对pRBC摄取之间的关系，研究所涉及的受体并比较恶性疟原虫的不同临床分离株诱导杯形成的能力;以及2）确定pRBC诱导的杯和摄取如何有助于EC屏障的破坏，这是通过打开连接的信号传导途径还是通过诱导细胞死亡发生。我们的长期目标是了解pRBC如何诱导内皮激活和血脑屏障破坏，以改善治疗发展。在白细胞TEM途径的背景下表征内皮pRBC摄取不仅是一个新的想法，而且探索pRBC摄取对于理解和控制脑疟疾病理学具有重要意义。

 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.