A Cellular Receptor for New World Arenaviruses

新世界沙粒病毒的细胞受体

• 批准号: 8321447
• 负责人: Hyeryun Choe
• 金额: $ 5.08万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321447
• 关键词: Accounting; Acute; Address; American; Arenavirus; Binding; Bolivian Hemorrhagic Fever Virus; Categories; Cells; Chimera organism; Collaborations; Complex; Disease; Event; Feedback; Frequencies; Funding; Glycoproteins; Human; Human Cell Line; In Vitro; Infection; Iron; Knock-in Mouse; Laboratories; Libraries; Light; Link; Methods; Modeling; Mus; National Institute of Allergy and Infectious Disease; North America; Orthologous Gene; Pathogenicity; Phase; Physiological; Play; Randomized; Relative (related person); Risk; Rodent; Role; Severities; South America; Structure; Tacaribe Complex Viruses; Testing; Up-Regulation; Variant; Viral; Viral Hemorrhagic Fevers; Virulence; Virus; Virus Receptors; Zoonoses; base; cost; fitness; human TFRC protein; human disease; human transferrin receptor 1; in vivo; inhibitor/antagonist; mouse transferrin receptor 1; novel; pathogen; receptor; receptor binding; response; transmission process

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.

描述（由申请人提供）：五种新世界沙粒病毒可引起人类致命性出血热。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，即人转铁蛋白受体1（TfR 1）。我们还定位了这些病毒结合的TfR 1结构域，并确定了人类TfR 1和其宿主物种的TfR 1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，两种与人出血热沙粒病毒密切相关的非致病性病毒有效地利用了各自宿主物种的TfR 1直系同源物，但不结合或使用人TfR 1。尽管如此，这些病毒通过TfR 1非依赖性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TfR 1复合的马丘波病毒入口糖蛋白GP 1的结构。总的来说，我们以前的研究清楚地表明，（1）使用人TfR 1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）非致病性病毒获得使用人TfR 1只需要在其进入糖蛋白GP的受体结合区发生适度变化。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沙粒病毒包括可以使用人类TfR 1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，用于评估给定沙粒病毒变体获得使用人TfR 1能力的相对可能性。我们还将解决其他GP 1/TfR 1复合物的结构，为解释我们基于库的研究结果提供框架。其次，人类TfR 1的使用与出血热密切相关的生理基础是什么？我们探讨的假设，TfR 1上调感染，特别是作为铁螯合的结果，在放大病毒复制中起着关键作用。为了验证这一假设，我们将开发一种新的新世界沙粒病毒感染的小鼠模型。总的来说，我们的研究将突出可能特别关注的循环沙粒病毒，建立一个新的感染模型，并阐明一个破坏性的反馈机制，有助于沙粒病毒出血热。