Binding Mechanisms in P.falciparum Cerebral Malaria

描述(申请人提供)：脑型疟疾是疟疾感染的一种致命并发症，与恶性疟原虫感染的红细胞(IES)在脑微血管中聚集有关，但发病的分子机制仍不清楚。IE结合主要由称为var基因或恶性疟原虫红细胞膜蛋白1(PfEMP1)的一大家族蛋白质介导。我们的团队和其他人最近发现，特定的PfEMP1蛋白，称为DC8和DC13，编码大脑结合活性，并与儿童脑型疟疾感染有关。在这个项目中，我们将描述介导DC8感染的红细胞与脑内皮细胞黏附的宿主结合伙伴，以及可能由恶性疟原虫细胞黏附启动的信号通路。我们将进一步研究DC8和DC13是否是介导与脑内皮细胞高亲和力结合的主要VAR产物，并定义关键相互作用残基TAT介导寄生虫与新的脑受体黏附候选者的黏附。这些研究将有助于详细描述恶性疟原虫-IE在脑内隔离的分子机制，并确定可能参与脑疟疾发病机制的内皮信号通路。

DESCRIPTION (provided by applicant): Cerebral malaria is a deadly complication of malaria infection associated with the accumulation of P. falciparum infected erythrocytes (IEs) in cerebral microvasculature, but the molecular mechanisms of pathogenesis are still poorly understood. IE binding is primarily mediated by a large family of proteins, called the var genes or P. falciparum erythrocyte membrane protein 1 (PfEMP1). Our group and others recently discovered that specific PfEMP1 proteins, termed DC8 and DC13, encode cerebral binding activity and are associated with cerebral malaria infections in children. In this project, we will characterize the host binding partners that mediate DC8-infected erythrocyte adhesion to brain endothelial cells and characterize signaling pathways that may be initiated by P. falciparum cytoadhesion. We will further investigate if DC8 and DC13 are the principal var products that mediate high affinity binding to brain endothelial cells and define critical interaction residues tat mediate parasite adhesion to a novel brain receptor adhesion candidate. These studies will contribute to a detailed characterization of the molecular mechanisms associated with P. falciparum-IE sequestration in brain and define endothelial signaling pathways that may contribute to cerebral malaria pathogenesis.