Molecular Mechanisms in Pediatric Cerebral Malaria Pathogenesis and Immunity

项目摘要 人类疟疾寄生虫恶性疟原虫仍然是儿童最重要的原因之一 死亡率在世界上。脑型疟疾是恶性疟原虫感染最严重的并发症， 受感染的红细胞在脑微血管中的隔离。var基因或恶性疟原虫 红细胞膜蛋白1（PfEMP 1）是寄生虫的主要细胞粘附配体。虽然进展 在理解PfEMP 1蛋白的结构和功能方面取得了进展，PfEMP 1蛋白是寄生虫的关键配体， 参与脑结合的受体相互作用仍未建立。我们最近的研究表明， 脑型疟疾患者血液中的特定寄生虫粘附类型增加， 与内皮蛋白C受体（EPCR）的粘附可能会损害关键的抗凝剂和屏障保护作用， 通路此外，我们已经表明，高乳酸血症增加儿童脑型疟疾的死亡风险。 然而，在大脑中的寄生虫隔离方面仍然存在很大的知识差距，这在很大程度上是由于其难以接近 以及缺乏合适的体外模型。我们最近开发了一种创新技术， 人脑微血管，再现健康和疾病时的生理流动特征。我们 能够制造具有不同几何形状和管腔尺寸的3D微血管，这使我们能够研究 寄生虫粘附在一个单一的设备，以及调查的因素， 导致疟疾微血管阻塞。在这个项目中，我们将使用3D人脑微血管， 结合儿童脑型疟分离株研究疟原虫的嗜性， 脑，以确定感染的红细胞捕获和牢固粘附在脑内皮细胞上的精确步骤 细胞，以表征乳酸菌血症和寄生虫感染之间的潜在相互作用，并研究 脑型疟疾的抗体保护机制拟议的研究将增进我们对以下问题的了解： 恶性疟原虫在脑型疟中结合的分子机制和抗- 疾病免疫力。

PROJECT ABSTRACT The human malaria parasite Plasmodium falciparum remains one of the most important causes of childhood mortality in the world. Cerebral malaria, the most severe complication of P. falciparum infection, is caused by the sequestration of infected red blood cells in cerebral microvasculature. The var gene or P. falciparum erythrocyte membrane protein 1 (PfEMP1) is the major cytoadhesion ligand for the parasite. While progress has been made in understanding the structure and function of PfEMP1 proteins, the key parasite ligand- receptor interactions involved in cerebral binding remain unestablished. Our recent studies have shown that specific parasite adhesion types are increased in the blood of cerebral malaria patients, and that parasite adhesion to endothelial protein C receptor (EPCR) may impair a key anticoagulant and barrier protective pathway. Moreover, we have shown that hyperlactemia increases fatality risk in pediatric cerebral malaria. However, large knowledge gaps remain in parasite sequestration in brain, in large part due to its inaccessibility and the lack of appropriate in vitro models. We have recently developed an innovative technology using 3D human brain microvessels that recapitulates physiological flow characteristics in health and disease. We are able to fabricate 3D microvessels with different geometries and lumen dimensions, which allow us to study parasite adhesion across a range of flow velocities in a single device, as well as to investigate factors that contribute to microvascular obstruction in malaria. In this project, we will use 3D human brain microvessels in combination with parasite isolates from pediatric cerebral malaria cases to investigate parasite tropism for brain, to identify the precise steps of infected red blood cell capture and firm adhesion on brain endothelial cells, to characterize potential interactions between lactemia and parasite adhesiveness, and to investigate antibody protective mechanisms in cerebral malaria. The proposed studies will advance our understanding of the molecular mechanisms of P. falciparum binding in cerebral malaria and immune mechanisms in anti- disease immunity.