A Cellular Receptor for New World Arenaviruses

描述(申请人提供)：五种新大陆禽流感病毒可导致人类发生致命的出血热。在上一个资助周期中，我们确定了这些病毒的共同细胞受体--人转铁蛋白受体1(TfR1)。我们还定位了这些病毒结合的TfR1结构域，并确定了人类TfR1和它们宿主物种的TfR1同源物之间的关键共同点，这些共同点使得有效地传播给人类成为可能。我们进一步表明，两种与人类出血热病毒密切相关的非致病病毒有效地利用了它们各自宿主物种的TfR1同源物，但不结合或使用人TfR1。然而，这些病毒通过一种不依赖TfR1的机制有效地进入人类细胞。除了这些研究外，我们还合作确定了Machupo病毒与人TfR1复合的入口糖蛋白GP1的结构。总而言之，我们之前的研究表明：(1)使用人TfR1的能力，而不是感染人类细胞的能力，是新大陆阿拉伯病毒是否会导致人类出血热的关键决定因素，(2)非致病病毒使用人TfR1只需要对其进入糖蛋白GP的受体结合区进行轻微改变。我们目前的研究试图回答这些研究提出的两个问题。首先，在北美和南美流行的非致病性禽流感病毒包括可以利用人类TfR1的准种的可能性有多大？为了解决这个问题，我们开发了一种基于GP文库的方法，用于评估给定的ArenaVirus变体获得使用人类TfR1的能力的相对可能性。我们还将解决额外的GP1/TfR1复合体的结构，以提供一个框架来解释我们基于图书馆的研究结果。第二，人类TfR1的使用与出血热密切相关的生理基础是什么？我们探讨了这样的假设，即TfR1在对感染的反应中上调，特别是作为铁封存的结果，在放大病毒复制方面起着关键作用。为了验证这一假设，我们将开发一种新的新大陆阿拉伯病毒感染的小鼠模型。总而言之，我们的研究将突出可能引起特别关注的循环病毒，建立一种新的感染模型，并阐明导致病毒出血热的破坏性反馈机制。

DESCRIPTION (provided by applicant): Five New World arenaviruses cause fatal hemorrhagic fevers in humans. In the last funding cycle we identified the common cellular receptor for these viruses, human transferrin receptor 1 (TfR1). We also localized the TfR1 domain which these viruses bind, and identified key commonalities between the human TfR1 and TfR1 orthologs of their host species that made possible efficient transmission to humans. We further showed that two non-pathogenic viruses, closely related to human hemorrhagic fever arenaviruses, efficiently used the TfR1 orthologs of their respective host species, but did not bind or use human TfR1. These viruses nonetheless efficiently enter human cells through a TfR1- independent mechanism. In addition to these studies, we collaborated to determine the structure of the entry glycoprotein GP1 of the Machupo virus, complexed to human TfR1. Collectively our previous studies made clear that (1) ability to use human TfR1, not the ability to infect human cells, is the key determinant in whether a New World arenavirus will cause a human hemorrhagic fever, (2) gain of use of human TfR1 by non-pathogenic viruses will require only modest changes in the receptor-binding regions of their entry glycoproteins, GP. Our current studies seek to answer two questions raised by these studies. First, how likely is it that non- pathogenic arenaviruses circulating in North and South America include quasispecies that can use human TfR1? To address this question we have developed a GP library-based approach for assessing the relative likelihood that a given arenavirus variant will gain the ability to use human TfR1. We will also solve the structures of additional GP1/TfR1 complexes to provide a framework for interpreting the results of our library-based studies. Second, what is the physiological basis for the close relationship between human TfR1 use and hemorrhagic fever? We explore the hypothesis that TfR1 upregulation in response to infection, and in particular as a consequence of iron sequestration, plays a pivotal role in amplifying viral replication. To test this hypothesis we will develop a novel murine model of New World arenaviral infection. Collectively our studies will highlight circulating arenaviruses that may be of special concern, establish a novel model of infection, and illuminate a destructive feedback mechanism contributing to arenaviral hemorrhagic fevers.