The Role of IFITM3 in the Anti-viral Host Response

描述（由申请人提供）：流感疫情对世界卫生造成巨大损失。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可能构成灾难性的全球健康风险。像所有病毒一样，甲型流感病毒利用宿主因子进行复制。为了抵御这种剥削，宿主调动各种因子来对抗病毒。一种独特的蛋白质信号分子，干扰素（ifn），在细胞和组织水平上协调了这种抗病毒反应的很大一部分。干扰素刺激导致超过2000个基因产物在干扰素刺激后被差异调节。为了寻找甲型H1N1流感病毒感染的宿主细胞修饰因子，我们完成了大规模的基因筛选，发现了几个在降低甲型流感病毒感染中重要的蛋白，包括干扰素诱导的跨膜蛋白3 （IFITM3）。IFITM3的缺失导致多种细胞系中病毒复制升高，并被证明对IFN诱导的病毒抗性至关重要，占IFN保护能力的50%至80%。IFITM3在人类中属于4个密切相关的蛋白家族，在小鼠中属于5个蛋白家族。本应用旨在阐明IFITM蛋白在宿主对甲型流感病毒感染的反应中的作用。成功实现本提案的目标将提供对IFITM蛋白作用的深入了解，并将使我们更充分地了解先天干扰素对病毒的反应。与公共卫生的相关性：甲型流感病毒是对世界卫生的威胁。我们之前的研究表明，IFITM蛋白在阻断甲型流感病毒感染中发挥重要作用。我们正在研究IFITM3如何减少甲型流感病毒感染，并试图找到利用这一知识抑制病毒感染的方法。

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.