PB2 Residue 158 Is a Pathogenic Determinant of Pandemic H1N1 and H5 Influenza A Viruses in Mice
PB2 Residue 158 Is a Pathogenic Determinant of Pandemic H1N1 and H5 Influenza A Viruses in Mice
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DOI：
10.1128/jvi.01694-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Wentworth, David E.
中科院分区：
文献类型：
--
作者：
Zhou, Bin;Li, Yan;Wentworth, David E.
甲型流感病毒是人类和动物病原体，可导致轻度至重度的发病和死亡。2009年H1N1流感大流行是由一种含有最初在人、禽和猪病毒宿主中传播的基因片段的可抵抗的H1N1亚型（H1N1 pdm）流感病毒的出现引起的。H1N1 pdm病毒在人类和其他哺乳动物中复制和致病的分子决定因素知之甚少。因此，我们开始阐明病毒决定因素的发病机制，这种新的recritantan使用小鼠模型。我们发现PB 2基因第158位残基的谷氨酸-甘氨酸取代（PB 2-E158 G）增加了亲本H1N1 pdm病毒的发病率和死亡率。在人类细胞中的微型基因组复制测定和在小鼠组织中的病毒滴定的结果表明，PB 2-E158 G是一个致病决定因素，因为它显着增加病毒复制速率。PB 2-E158 G感染小鼠肺中的病毒载量比野生型病毒高1,300倍。我们的数据还表明，PB 2-E158 G对H1N1 pdm病毒的RNA复制和致病性的影响比已知的致病决定因子PB 2-E627 K强得多。值得注意的是，PB 2-E158 G取代还改变了小鼠中两种禽H5病毒的致病型，表明该残基影响遗传上不同的甲型流感病毒，并表明PB 2的该区域可能是新的抗病毒靶点。总的来说，本研究中提供的数据表明，PB 2-E158 G是小鼠模型中甲型流感病毒的新致病决定因素。我们推测，PB 2-E158 G可能是重要的鸟类PB 2基因的适应其他哺乳动物，和BLAST序列分析确定了一个自然发生的人H1N1 pdm分离，有这种取代。因此，未来的监测工作应包括PB 2的这一区域的审查，因为它对发病机制的潜在影响。
Influenza A viruses are human and animal pathogens that cause morbidity and mortality, which range from mild to severe. The 2009 H1N1 pandemic was caused by the emergence of a reassortant H1N1 subtype (H1N1pdm) influenza A virus containing gene segments that originally circulated in human, avian, and swine virus reservoirs. The molecular determinants of replication and pathogenesis of H1N1pdm viruses in humans and other mammals are poorly understood. Therefore, we set out to elucidate viral determinants critical to the pathogenesis of this novel reassortant using a mouse model. We found that a glutamate-to-glycine substitution at residue 158 of the PB2 gene (PB2-E158G) increased the morbidity and mortality of the parental H1N1pdm virus. Results from mini-genome replication assays in human cells and virus titration in mouse tissues demonstrated that PB2-E158G is a pathogenic determinant, because it significantly increases viral replication rates. The virus load in PB2-E158G-infected mouse lungs was 1,300-fold higher than that of the wild-type virus. Our data also show that PB2-E158G had a much stronger influence on the RNA replication and pathogenesis of H1N1pdm viruses than PB2-E627K, which is a known pathogenic determinant. Remarkably, PB2-E158G substitutions also altered the pathotypes of two avian H5 viruses in mice, indicating that this residue impacts genetically divergent influenza A viruses and suggesting that this region of PB2 could be a new antiviral target. Collectively, the data presented in this study demonstrate that PB2-E158G is a novel pathogenic determinant of influenza A viruses in the mouse model. We speculate that PB2-E158G may be important in the adaptation of avian PB2 genes to other mammals, and BLAST sequence analysis identified a naturally occurring human H1N1pdm isolate that has this substitution. Therefore, future surveillance efforts should include scrutiny of this region of PB2 because of its potential impact on pathogenesis.