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Severe malaria is associated with parasite binding to endothelial protein C receptor

机译：严重疟疾与寄生虫结合内皮蛋白C受体有关

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摘要

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 (PfEMPl) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMPl subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMPl. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRal) of DC8 and group A PfEMPl subfamilies, and that CIDRal interferes with protein C binding to EPCR. This PfEMPl 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.
机译：在严重的儿童疟疾的发病机理中，隔离恶性疟原虫感染的红细胞是宿主血管中的关键触发事件，每年导致约一百万例死亡。通过恶性疟原虫红细胞膜蛋白1（PfEMP1）家族的成员与内皮细胞衬里上的受体之间的特异性相互作用来介导螯合。儿童期严重疟疾与含有结构域盒（DC）8和13的特定PfEMP1亚型的表达有关（参考文献3），但是表达这些蛋白的寄生虫的内皮受体尚不清楚。在这里，我们确定了介导活化蛋白C的细胞保护作用的内皮蛋白C受体（EPCR）作为DC8和DC13 PfEMP1的内皮受体。我们显示EPCR结合是通过DC8和A组PfEMP1亚家族的氨基末端富含半胱氨酸的域间区域（CIDRal）介导的，并且CIDRal干扰了蛋白C与EPCR的结合。这种PfEMP1粘附特性将恶性疟原虫细胞粘附与参与抗凝和内皮细胞保护途径的宿主受体联系起来，对理解疟疾病理学和开发新的疟疾干预措施具有重要意义。

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  • 来源
    《Nature》 |2013年第7455期|502-505|共4页
  • 作者

    Louise Turner; Thomas Lavstsen; Sanne S. Berger; Christian W. Wang; Jens E. V. Petersen; Marion Avril; Andrew J. Brazier; Jim Freeth; Jakob S. Jespersen; Morten A. Nielsen; Pamela Magistrado; John Lusingu; Joseph D. Smith; Matthew K. Higgins; Thor G. Theander;

  • 作者单位

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Seattle Biomedical Research Institute, Seattle, Washington 98109-5219, USA.;

    Seattle Biomedical Research Institute, Seattle, Washington 98109-5219, USA.;

    Retrogenix, Crown House, Bingswood Estate, Whaley Bridge, High Peak SK23 7LY, UK.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

    National Institute of Medical Research, Tanga Centre, Tanga, Tanzania;

    National Institute of Medical Research, Tanga Centre, Tanga, Tanzania;

    Seattle Biomedical Research Institute, Seattle, Washington 98109-5219, USA, Department of Global Health, University of Washington, Seattle, Washington 98195, USA.;

    Department of Biochemistry, University of Oxford, South Parks Road, Oxford 0X1 3QU, UK;

    Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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