A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence.
A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence.
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DOI：
10.1371/journal.ppat.0030141
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发表时间：
2007-10-05
期刊：
影响因子：
6.7
通讯作者：
Palese P
中科院分区：
文献类型：
--
作者：
Conenello GM;Zamarin D;Perrone LA;Tumpey T;Palese P
甲型流感病毒的促凋亡PB 1-F2蛋白已被证明有助于小鼠模型中的发病机制。全长PB 1-F2的表达增加了甲型流感病毒的发病机制，导致体重减轻、病毒清除减慢和肺中病毒滴度增加。比较香港1997年H5 N1爆发的病毒后，在PB 1-F2序列的第66位发现一个与致病性相关的氨基酸变化（N66 S）。在1918年大流行A/Brevig使命/18病毒的PB 1-F2蛋白中也发现了相同的氨基酸变化（N66 S）。用含有来自HK/156/97：WH和WH N66 S的PB 1片段的A/WSN/33流感病毒背景创建了两种同基因重组嵌合病毒。在感染WH N66 S病毒的小鼠中，与感染WH病毒的小鼠相比，通过体重减轻和存活率降低测量的致病性增加，并且病毒复制增加100倍。1918年大流行毒株A/Brevig使命/18在PB 1-F2（S66 N）中用致病性降低突变重建。所得的1918 S66 N病毒在小鼠中减毒，具有比野生型病毒低3个对数的50%致死剂量，并且在小鼠中引起更少的发病率和死亡率。与野生型1918病毒感染的小鼠相比，1918 S66 N感染的小鼠的病毒肺滴度也降低。此外，在位置66处具有S的两种病毒（WH N66 S和wt 1918）在感染小鼠的肺中诱导升高的细胞因子水平。总之，这些数据表明，PB 1-F2中的单个氨基酸取代可导致病毒致病性增加，并且可能是导致1918年大流行病毒的高致死率的因素之一。PB 1-F2是最近发现的由甲型流感病毒产生的蛋白质。先前已经表明，PB 1-F2存在于线粒体中，在那里它诱导细胞死亡;我们的实验室已经证明，PB 1-F2是小鼠感染模型中发病机制的贡献者。为了进一步研究PB 1-F2，我们检测了高致病性禽流感病毒株，并定位了一个似乎与小鼠死亡增加相关的氨基酸变化。我们研究了两种不同病毒PB 1-F2中66位氨基酸的变化。使用具有来自H5 N1病毒的PB 1基因的重组病毒以及完全重建的1918年大流行病毒。在这项研究中，我们发现在高致病性甲型流感病毒分离株中发现的PB 1-F2突变导致非致病性病毒在小鼠中诱发疾病。此外，我们发现，增加的致病性与肺中更高水平的病毒和细胞因子有关。我们得出结论，PB 1-F2确实影响致病性，并且位置66似乎在促成小鼠模型中PB 1-F2的作用中起重要作用。
The proapoptotic PB1-F2 protein of influenza A viruses has been shown to contribute to pathogenesis in the mouse model. Expression of full-length PB1-F2 increases the pathogenesis of the influenza A virus, causing weight loss, slower viral clearance, and increased viral titers in the lungs. After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus. Two isogenic recombinant chimeric viruses were created with an influenza A/WSN/33 virus background containing the PB1 segment from the HK/156/97: WH and WH N66S. In mice infected with WH N66S virus there was increased pathogenicity as measured by weight loss and decreased survival, and a 100-fold increase in virus replication when compared to mice infected with the WH virus. The 1918 pandemic strain A/Brevig Mission/18 was reconstructed with a pathogenicity-reducing mutation in PB1-F2 (S66N). The resultant 1918 S66N virus was attenuated in mice having a 3-log lower 50% lethal dose and caused less morbidity and mortality in mice than the wild-type virus. Viral lung titers were also decreased in 1918 S66N–infected mice compared with wild-type 1918 virus–infected mice. In addition, both viruses with an S at position 66 (WH N66S and wt 1918) induced elevated levels of cytokines in the lungs of infected mice. Together, these data show that a single amino acid substitution in PB1-F2 can result in increased viral pathogenicity and could be one of the factors contributing to the high lethality seen with the 1918 pandemic virus. PB1-F2 is the most recently discovered protein produced by the influenza A virus. It has been previously shown that PB1-F2 is present in the mitochondria, where it induces cell death; our laboratory has demonstrated that PB1-F2 is a contributor to pathogenesis in the mouse model of infection. To study PB1-F2 further, we examined highly pathogenic strains of avian influenza virus and located an amino acid change that seemed to be associated with increased death in mice. We studied this amino acid change in PB1-F2 at position 66 in two different viruses. A recombinant virus that has a PB1 gene from an H5N1 virus was used as well as a fully reconstructed 1918 pandemic virus. In this study, we show that a mutation in PB1-F2 found in highly pathogenic influenza A virus isolates causes nonpathogenic viruses to induce disease in mice. In addition, we show that the increased pathogenicity is associated with higher levels of virus and cytokines in the lungs. We conclude that PB1-F2 does affect pathogenicity, and that position 66 seems to play an important role in contributing to the effects of PB1-F2 in the mouse model.
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影响因子：
120.7
作者：
Thompson, WW;Shay, DK;Fukuda, K
通讯作者：
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DOI：
10.20506/rst.14.3.880
发表时间：
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期刊：
REVUE SCIENTIFIQUE ET TECHNIQUE DE L OFFICE INTERNATIONAL DES EPIZOOTIES
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