Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida, USA.
Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida, USA
J Virol. 2014 Aug;88(16):9418-28. doi: 10.1128/JVI.01112-14. Epub 2014 Jun 11.
At least five New World (NW) arenaviruses cause hemorrhagic fevers in South America. These pathogenic clade B viruses, as well as nonpathogenic arenaviruses of the same clade, use transferrin receptor 1 (TfR1) of their host species to enter cells. Pathogenic viruses are distinguished from closely related nonpathogenic ones by their additional ability to utilize human TfR1 (hTfR1). Here, we investigate the receptor usage of North American arenaviruses, whose entry proteins share greatest similarity with those of the clade B viruses. We show that all six North American arenaviruses investigated utilize host species TfR1 orthologs and present evidence consistent with arenavirus-mediated selection pressure on the TfR1 of the North American arenavirus host species. Notably, one of these viruses, AV96010151, closely related to the prototype Whitewater Arroyo virus (WWAV), entered cells using hTfR1, consistent with a role for a WWAV-like virus in three fatal human infections whose causative agent has not been identified. In addition, modest changes were sufficient to convert hTfR1 into a functional receptor for most of these viruses, suggesting that a minor alteration in virus entry protein may allow these viruses to use hTfR1. Our data establish TfR1 as a cellular receptor for North American arenaviruses, highlight an "arms race" between these viruses and their host species, support the association of North American arenavirus with fatal human infections, and suggest that these viruses have a higher potential to emerge and cause human diseases than has previously been appreciated.
hTfR1 use is a key determinant for a NW arenavirus to cause hemorrhagic fevers in humans. All known pathogenic NW arenaviruses are transmitted in South America by their host rodents. North American arenaviruses are generally considered nonpathogenic, but some of these viruses have been tentatively implicated in human fatalities. We show that these North American arenaviruses use the TfR1 orthologs of their rodent host species and identify TfR1 polymorphisms suggesting an ongoing "arms race" between these viruses and their hosts. We also show that a close relative of a North American arenavirus suggested to have caused human fatalities, the Whitewater Arroyo species complex virus AV96010151, uses human TfR1. Moreover, we present data that imply that modest changes in other North American arenaviruses might allow these viruses to infect humans. Collectively, our data suggest that North American arenaviruses have a higher potential to cause human disease than previously assumed.
至少有五种新域（NW）沙粒病毒会导致南美洲出血热。这些致病的 B 谱系病毒以及同一谱系的非致病沙粒病毒，利用宿主物种的转铁蛋白受体 1（TfR1）进入细胞。与密切相关的非致病性病毒相比，致病性病毒的额外能力是利用人类转铁蛋白受体 1（hTfR1）。在这里，我们研究了北美的沙粒病毒的受体使用情况，其进入蛋白与 B 谱系病毒的进入蛋白具有最大的相似性。我们表明，所有六种被调查的北美沙粒病毒都利用宿主物种 TfR1 同源物，并提供了一致的证据，表明沙粒病毒对北美沙粒病毒宿主物种的 TfR1 存在选择压力。值得注意的是，其中一种病毒 AV96010151 与原型白水溪病毒（WWAV）密切相关，使用 hTfR1 进入细胞，这与 WWAV 样病毒在三种致命人类感染中的作用一致，而导致这些感染的病原体尚未确定。此外，对 hTfR1 进行适度改变足以使其成为大多数这些病毒的功能性受体，这表明病毒进入蛋白的微小改变可能使其能够利用 hTfR1。我们的数据确立了 TfR1 作为北美的沙粒病毒的细胞受体，突出了这些病毒与其宿主物种之间的“军备竞赛”，支持了北美的沙粒病毒与致命人类感染的关联，并表明这些病毒比以前认为的更有可能出现并导致人类疾病。
hTfR1 的使用是 NW 沙粒病毒在人类中引起出血热的关键决定因素。所有已知的致病性 NW 沙粒病毒都是通过南美洲的宿主啮齿动物传播的。北美沙粒病毒通常被认为是非致病性的，但其中一些病毒被暂时牵连到人类死亡事件中。我们表明，这些北美的沙粒病毒使用其啮齿动物宿主的 TfR1 同源物，并鉴定出 TfR1 多态性，表明这些病毒与其宿主之间正在进行“军备竞赛”。我们还表明，一种被认为导致人类死亡的北美的沙粒病毒的近亲，即白水溪种复合体病毒 AV96010151，使用人类 TfR1。此外，我们提供的数据表明，其他北美的沙粒病毒的适度改变可能会使这些病毒感染人类。总的来说，我们的数据表明，北美的沙粒病毒比以前认为的更有可能导致人类疾病。
