IFITM3 restricts the morbidity and mortality associated with influenza.
IFITM3 restricts the morbidity and mortality associated with influenza.
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DOI：
10.1038/nature10921
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发表时间：
2012-03-25
期刊：
影响因子：
64.8
通讯作者：
Kellam, Paul
中科院分区：
文献类型：
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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
2009年H1N1流感大流行显示了一种新型呼吸道病毒传播的速度，以及一般轻度感染在一部分人群中引起严重发病和死亡的能力。最近的体外研究表明，干扰素诱导跨膜（IFITM）蛋白家族成员有效地限制了多种致病病毒的复制。IFITM蛋白的体外效应的幅度和广度表明，它们对于对这些病毒（包括流感病毒）的内在抗性至关重要。使用基因敲除小鼠模型，我们现在直接测试这一假设，并发现IFITM 3是必不可少的防御宿主对甲型流感病毒在体内。当用正常低致病性流感病毒攻击时，缺乏Ifitm 3的小鼠表现出暴发性病毒性肺炎，这反映了1918年高致病性“西班牙”流感造成的破坏。在体外也观察到类似的病毒复制增加，通过重新引入Ifitm 3来挽救保护作用。为了检测IFITM 3在人类流感病毒感染中的作用，我们评估了因季节性或大流行性H1N1/09流感病毒住院的个体的IFITM 3等位基因。我们发现，统计学上显著数量的住院受试者显示出改变剪接受体位点的次要IFITM 3等位基因（SNP rs 12252-C）的富集，功能测定显示次要CC基因型IFITM 3在体外具有降低的流感病毒限制。总之，这些数据表明，单一内在免疫效应子IFITM 3的作用深刻地改变了小鼠和人类中流感病毒感染的过程。
The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recentin vitrostudies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses,,,,,,. Both the magnitude and breadth of the IFITM proteins’in vitroeffects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virusin vivo. Mice lackingIfitm3display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza,. Similar increased viral replication is seenin vitro, with protection rescued by the re-introduction ofIfitm3. To test the role of IFITM3 in human influenza virus infection, we assessed theIFITM3alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minorIFITM3allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restrictionin vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
64.8
作者：
Kobasa, D;Takada, A;Kawaoka, Y
通讯作者：
Kawaoka, Y
影响因子：
7
作者：
Fukuyama S;Kawaoka Y
通讯作者：
Kawaoka Y
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
7
作者：
Nielsen, R;Williamson, S;Bustamante, C
通讯作者：
Bustamante, C