Severe malaria is associated with parasite binding to endothelial protein C receptor.
Severe malaria is associated with parasite binding to endothelial protein C receptor.
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恶性疟原虫感染的红细胞在宿主血管中的隔离是严重儿童疟疾发病机制中的一个关键触发事件。儿童疟疾每年造成约100万人死亡。这种隔离是由恶性疟原虫红细胞膜蛋白1 （PfEMP1）家族成员与内皮细胞受体之间的特异性相互作用介导的。严重疟疾与含有域盒（DC） 8和13的特定PfEMP1亚型的表达有关，但表达这些蛋白的寄生虫的内皮受体尚不清楚。本研究发现，介导活化蛋白C细胞保护作用的内皮蛋白C受体（EPCR）是DC8和DC13 PfEMP1的内皮受体。我们发现EPCR的结合是通过DC8和A组PfEMP1亚家族的n端富含半胱氨酸的结构域间区（CIDRα1）介导的，并且CIDRα1干扰蛋白C与EPCR的结合。这种PfEMP1粘附特性将恶性疟原虫细胞粘附到参与抗凝和内皮细胞保护途径的宿主受体上，并对理解疟疾病理和开发新的疟疾干预措施具有重要意义。
Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 13, but the endothelial receptor for parasites expressing these proteins was unknown. Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the N-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways and has implications for understanding malaria pathology and the development of new malaria interventions.