Binding Mechanisms in P.falciparum Cerebral Malaria

描述（由申请人提供）：脑型疟疾是疟疾感染的致命并发症，与恶性疟原虫感染的红细胞（IE）在脑微血管中的积累有关，但发病机制的分子机制仍知之甚少。IE结合主要由称为var基因或恶性疟原虫红细胞膜蛋白1（PfEMP 1）的蛋白质大家族介导。我们的团队和其他人最近发现，特定的PfEMP 1蛋白，称为DC 8和DC 13，编码脑结合活性，并与儿童脑疟疾感染有关。在这个项目中，我们将表征介导DC 8感染的红细胞粘附到脑内皮细胞的宿主结合伴侣，并表征可能由恶性疟原虫细胞粘附启动的信号通路。我们将进一步研究DC 8和DC 13是否是介导与脑内皮细胞高亲和力结合的主要var产物，并确定介导寄生虫粘附到新的脑受体粘附候选物的关键相互作用残基。这些研究将有助于详细描述与恶性疟原虫-IE在脑中隔离相关的分子机制，并定义可能有助于脑型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.