A Cellular Receptor for New World Arenaviruses

描述(申请人提供)：禽流感病毒可引起人类严重的病毒性出血热。根据误用的可能性和引起疾病的严重程度，五种阿拉伯病毒被归类为NIAID A类病原体：淋巴细胞性脉络膜脑膜炎(LCM)、拉萨病毒、瓜纳里托病毒、马丘波病毒和朱宁病毒。LCM和Lassa病毒是东半球的一种利用细胞受体--营养不良聚糖进入细胞的病毒。瓜纳里托病毒、马丘波病毒和朱宁病毒都是新世界出血热病毒，被认为使用共同的受体，但这种受体尚未确定。在初步数据中，我们证明了转铁蛋白受体1(Tfr1)和马丘波病毒的进入糖蛋白(GP)之间存在高亲和力。人Tfr1显著提高了Machupo或Junin伪病毒(而不是Lassa伪病毒)感染弱允许的仓鼠细胞系的效率。抗人Tfr1抗体可阻止Machupo假病毒进入人细胞系，而Lassa假病毒不能进入人细胞系，而对照抗体则不能。我们的数据表明，Tfr1是新世界出血热病毒的专有细胞受体。我们的目标是：(1)充分表征Tfr1和Tfr2在一系列ArenaVirus进入过程中的作用，(2)确定Tfr1和Gp高亲和力结合的决定因素，(3)表征Tfr1物种变异在ArenaVirus进入过程中的作用，(4)描述可溶性Tfr1和各种抗Tfr1抗体对进入过程的影响，(5)描述铁和Tfr1相关蛋白在ArenaVirus进入过程中的作用，(6)合作解决与Tfr1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禽流感病毒会导致人类出血热，并将有助于评估那些没有感染人类的病毒所构成的风险。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.