The Role of IFITM3 in the Anti-viral Host Response

描述(申请人提供)：流感流行对世界健康造成了巨大的损失。去年，一种新型甲型H1N1流感病毒株的出现引发了一场大流行，在全球范围内引发了疾病。此外，相关的甲型禽流感病毒株H5N1代表着潜在的灾难性全球健康风险。像所有病毒一样，甲型流感病毒利用宿主因素进行复制。为了防御这种利用，宿主动员各种因素来对抗病毒。一类不同的蛋白质信号分子，干扰素(IFN)，在细胞和组织水平上协调这种抗病毒反应的一大部分。干扰素刺激导致2000多个基因产物在干扰素刺激后受到差异调控。为了寻找甲型H1N1流感病毒感染的宿主细胞修饰物，我们完成了大规模的遗传筛选，并检测了几种在减少甲型流感病毒感染中起重要作用的蛋白质，包括干扰素诱导的跨膜蛋白3(IFITM3)的作用。IFITM3的缺失导致病毒在多个细胞系中复制增加，并被证明是干扰素诱导的病毒抵抗的关键，占干扰素保护能力的50%~80%。IFITM3属于人类四个密切相关的蛋白质家族和小鼠的五个蛋白质家族。该应用旨在阐明IFITM蛋白在宿主对甲型流感病毒感染反应中的作用。这项提议的目标的成功实现将提供对IFITM蛋白作用的深入了解，并将更充分地向我们提供关于病毒的先天干扰素反应的信息。与公共卫生相关：甲型流感病毒对世界健康构成威胁。我们以前的研究表明，IFITM蛋白在阻断甲型流感病毒感染方面发挥着重要作用。我们正在研究IFITM3如何降低甲型流感病毒感染，并试图找到利用这一知识抑制病毒感染的方法。 公共卫生相关性：甲型流感病毒是一种单链RNA病毒，会造成呼吸道疾病的流行。这些研究将确定IFITM3的S阻断甲型流感病毒感染能力的分子机制，并确定与IFITM3合作阻止病毒感染的蛋白质。这项工作将提高我们对IFITM蛋白如何抑制甲型流感病毒复制的理解，并可能为如何阻止并可能治疗甲型流感病毒感染提供洞察力。

DESCRIPTION (provided by applicant): Influenza epidemics exact a formidable toll on world health. Last year, the emergence of a novel influenza A H1N1 viral strain created a pandemic, producing illness around the globe. Additionally, the related avian influenza A viral strain, H5N1, represents a potentially catastrophic global health risk. Like all viruses, influenza A virus exploits host factors to replicate. To defend against this exploitation, the host mobilizes factors to confront the virus. A distinct class of protein signaling molecules, the interferons (IFNs), orchestrates a large component of this anti-viral response at both a cellular and organismal level. IFN stimulation results in over 2000 gene products being differentially regulated after IFN stimulation. To find host-cell modifiers of influenza A H1N1 viral infection, we completed a large scale genetic screen and detected several proteins which are important in decreasing influenza A virus infection, including a role for interferon-inducible trans-membrane protein 3 (IFITM3). The loss of IFITM3 resulted in elevated viral replication in multiple cell lines tested, and proved to be critical for IFN-induced viral resistance, accounting for 50% to 80% of IFN's protective ability. IFITM3 belongs to a family of four closely related proteins in humans, and five proteins in mice. This application aims to elucidate the role of the IFITM proteins in the host response to influenza A virus infection. Successful achievement of the aims of this proposal will provide in depth knowledge of the actions of the IFITM proteins and will inform us more fully on the innate interferon response to viruses. Relevance to Public Health: Influenza A virus is a threat to world health. Our previous studies have shown that the IFITM proteins play an important role in blocking influenza A virus infection. We are studying how IFITM3 decreases influenza A virus infection, and trying to find ways to use this knowledge to inhibit viral infections. PUBLIC HEALTH RELEVANCE: Influenza A virus is a single stranded RNA virus that creates epidemics of respiratory illness. The studies proposed here will determine the molecular mechanism underlying IFITM3's ability to block influenza A virus infection, and identify proteins that partner with IFITM3 to stop viral infection. This work will improve our understanding of how the IFITM proteins inhibit the replication of influenza A virus and will likely provide insight into how to stop and possibly treat influenza A virus infection.