A Cellular Receptor for New World Arenaviruses

描述（由申请方提供）：沙粒病毒引起人类严重病毒性出血热。五种沙粒病毒由于其误用的可能性和它们引起的疾病的严重性而被分类为NIAID A类病原体：淋巴细胞性脉络丛脑膜炎（LCM）、Lassa、Guanarito、Machupo和朱宁病毒。LCM和拉沙病毒是旧大陆沙粒病毒，使用细胞受体？肌营养不良聚糖进入细胞。Guanarito、Machupo和朱宁病毒都是新世界出血热沙粒病毒，被认为使用一种共同的受体，但这种受体尚未被鉴定。在初步的数据中，我们证明了转铁蛋白受体1（TFR 1）和入口糖蛋白（GP）的马丘波病毒之间的高亲和力协会。人Tfr 1显著增加了Machupo或朱宁假病毒（但不是Lassa假病毒）感染弱许可仓鼠细胞系的效率。进入人细胞系的Machupo假病毒，但不是拉沙假病毒，被取消的抗人Tfr 1抗体，但不是由对照抗体。我们的数据表明，Tfr1是一个专性细胞受体的新世界出血热沙粒病毒。我们的目标是：（1）充分表征Tfr 1和Tfr 2在大量沙粒病毒进入过程中的作用，（2）鉴定Tfr 1和GP决定簇的高亲和力结合，（3）表征Tfr 1物种变异在沙粒病毒进入过程中的作用，（4）描述可溶性Tfr 1和各种抗Tfr 1抗体对进入的作用，（5）描述铁和Tfr 1相关蛋白在沙粒病毒进入中的作用，（6）合作解决与Tfr 1结合的GP的结构。 这些研究将阐明为什么一些但不是所有的沙粒病毒会引起人类出血热，并将有助于评估那些没有感染人类的沙粒病毒所带来的风险。他们还将为南美出血热的蛋白质和小分子疗法的开发做出贡献。

DESCRIPTION (provided by applicant): Arenaviruses cause severe viral hemorrhagic fevers in humans. Five arenaviruses have been classified as NIAID Category A pathogens due to their potential for misuse and the severity of the disease they cause: lymphocytic choriomeningitis (LCM), Lassa, Guanarito, Machupo, and Junin viruses. LCM and Lassa viruses are Old World arenaviruses that use the cellular receptor ?-dystroglycan to enter cells. Guanarito, Machupo, and Junin viruses, all New World hemorrhagic fever arenaviruses, are thought to use a common receptor, but this receptor has not been identified. In preliminary data, we demonstrate a high affinity association between transferrin receptor 1 (Tfr1) and the entry glycoprotein (GP) of Machupo virus. Human Tfr1 markedly increased the efficiency with which Machupo or Junin pseudoviruses, but not Lassa pseudovirus, infected a weakly permissive hamster cell line. Entry into human cell lines of Machupo pseudovirus, but not Lassa pseudovirus, was abolished by anti-human Tfr1 antibody, but not by a control antibody. Our data indicate that Tfr1 is an obligate cellular receptor for New World hemorrhagic fever arenaviruses. Our aims are to: (1) fully characterize the role of Tfr1 and Tfr2 in the entry processes of an extensive panel of arenaviruses, (2) identify Tfr1 and GP determinants of their high affinity association, (3) characterize the role of Tfr1 species variation in arenaviral entry, (4) describe the effect of soluble Tfr1, and of various anti-Tfr1 antibodies on entry, (5) describe the role of iron and of Tfr1- associated proteins in arenaviral entry, (6) collaborate to solve the structure of GP bound to Tfr1. These studies will shed light on why some, but not all arenaviruses cause hemorrhagic fevers in humans, and will help assess the risk posed by those that have not infected humans. They will also contribute to the development of protein and small-molecule therapeutics for South American hemorrhagic fevers.