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The Role of IFITM3 in the Anti-viral Host Response

IFITM3 在抗病毒宿主反应中的作用

基本信息

批准号：
8901911
负责人：
ABRAHAM L BRASS
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901911
关键词：
Accounting Achievement Antiviral Agents Antiviral Response Avian Influenza Cell Count Cell Line Cells Cellular biology Dengue Virus Epidemic Family Genes Genetic Genetic Screening Genome Goals Human IFITM1 gene Immune Immune response Immunity Immunology Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Integral Membrane Protein Integration Host Factors Interferons Knowledge Learning Life Cycle Stages Mediating Membrane Proteins Molecular Mus Natural Immunity Outcome Play Proteins Public Health RNA Viruses Regulation Resistance Risk Role Signaling Molecule Small Interfering RNA Structure System Testing Viral Viral Physiology Virus Virus Diseases Virus Replication West Nile virus Work World Health cytokine functional genomics global health improved influenza epidemic insight novel pandemic disease pathogen respiratory response viral resistance virology

项目摘要

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.

描述（由申请人提供）：流感流行对世界健康造成了巨大损失。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 代表着潜在的灾难性全球健康风险。与所有病毒一样，甲型流感病毒利用宿主因子进行复制。为了抵御这种利用，宿主会动员各种因素来对抗病毒。干扰素 (IFN) 是一类独特的蛋白质信号分子，在细胞和有机体水平上协调这种抗病毒反应的重要组成部分。 IFN 刺激导致 2000 多种基因产物在 IFN 刺激后受到差异性调节。为了找到甲型 H1N1 流感病毒感染的宿主细胞修饰剂，我们完成了大规模遗传筛选，并检测到了几种对减少甲型流感病毒感染很重要的蛋白质，其中包括干扰素诱导跨膜蛋白 3 (IFITM3) 的作用。 IFITM3 的缺失导致多个测试细胞系中病毒复制增加，并被证明对 IFN 诱导的病毒耐药性至关重要，占 IFN 保护能力的 50% 至 80%。 IFITM3 属于人类中四种密切相关的蛋白质家族，以及小鼠中的五种蛋白质。该应用旨在阐明 IFITM 蛋白在宿主对甲型流感病毒感染的反应中的作用。该提案目标的成功实现将提供对 IFITM 蛋白作用的深入了解，并使我们更全面地了解干扰素对病毒的先天反应。与公共卫生的相关性：甲型流感病毒对世界健康构成威胁。我们前期的研究表明，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 如何减少甲型流感病毒感染，并试图找到利用这些知识来抑制病毒感染的方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional Genomic Strategies for Elucidating Human-Virus Interactions: Will CRISPR Knockout RNAi and Haploid Cells?

DOI：
10.1016/bs.aivir.2015.11.001
发表时间：
2016
期刊：
Advances in virus research
影响因子：
0
作者：
Perreira JM;Meraner P;Brass AL
通讯作者：
Brass AL

IFITM3 restricts the morbidity and mortality associated with influenza.

DOI：
10.1038/nature10921
发表时间：
2012-03-25
期刊：
NATURE
影响因子：
64.8
作者：
Everitt, Aaron R.;Clare, Simon;Pertel, Thomas;John, Sinu P.;Wash, Rachael S.;Smith, Sarah E.;Chin, Christopher R.;Feeley, Eric M.;Sims, Jennifer S.;Adams, David J.;Wise, Helen M.;Kane, Leanne;Goulding, David;Digard, Paul;Anttila, Verneri;Baillie, J. Kenneth;Walsh, Tim S.;Hume, David A.;Palotie, Aarno;Xue, Yali;Colonna, Vincenza;Tyler-Smith, Chris;Dunning, Jake;Gordon, Stephen B.;Smyth, Rosalind L.;Openshaw, Peter J.;Dougan, Gordon;Brass, Abraham L.;Kellam, Paul
通讯作者：
Kellam, Paul

Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction.

DOI：
10.1016/j.celrep.2013.10.033
发表时间：
2013-11-27
期刊：
Cell reports
影响因子：
8.8
作者：
Lin TY;Chin CR;Everitt AR;Clare S;Perreira JM;Savidis G;Aker AM;John SP;Sarlah D;Carreira EM;Elledge SJ;Kellam P;Brass AL
通讯作者：
Brass AL

IFITMs restrict the replication of multiple pathogenic viruses.