A Cellular Receptor for New World Arenaviruses

描述（由申请人提供）：五种新世界沙粒病毒可引起人类致命的出血热。在上一个资助周期中，我们确定了这些病毒的常见细胞受体，即人转铁蛋白受体 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 与其宿主物种的 TfR1 直系同源物之间的关键共性，这些共性使得有效传播给人类成为可能。我们进一步表明，与人类出血热沙粒病毒密切相关的两种非致病性病毒有效地利用了各自宿主物种的 TfR1 直系同源物，但不结合或使用人类 TfR1。尽管如此，这些病毒仍然通过 TfR1 独立机制有效地进入人类细胞。除了这些研究之外，我们还合作确定了与人类 TfR1 复合的 Machupo 病毒入口糖蛋白 GP1 的结构。总的来说，我们之前的研究表明（1）使用人类 TfR1 的能力，而不是感染人类细胞的能力，是新世界沙粒病毒是否会引起人类出血热的关键决定因素，（2）非病原性病毒对人类 TfR1 的利用只需要对其进入糖蛋白 GP 的受体结合区进行适度的改变。我们当前的研究试图回答这些研究提出的两个问题。首先，在北美和南美传播的非致病性沙粒病毒中包含可以使用人类 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 库的方法，用于评估给定沙粒病毒变种获得使用人类 TfR1 的能力的相对可能性。我们还将解析其他 GP1/TfR1 复合物的结构，为解释我们基于图书馆的研究结果提供一个框架。其次，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：TfR1 因感染而上调，特别是铁隔离的结果，在放大病毒复制中发挥着关键作用。为了检验这一假设，我们将开发一种新世界沙病毒感染的新型小鼠模型。总的来说，我们的研究将重点关注可能值得特别关注的循环沙粒病毒，建立一种新型感染模型，并阐明导致沙粒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.