Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses.
Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses.
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DOI：
10.1371/journal.ppat.1005583
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Watanabe Y
中科院分区：
文献类型：
--
作者：
Arai Y;Kawashita N;Daidoji T;Ibrahim MS;El-Gendy EM;Takagi T;Takahashi K;Suzuki Y;Ikuta K;Nakaya T;Shioda T;Watanabe Y
禽流感病毒宿主范围向人类转变的一个主要决定因素是PB 2聚合酶蛋白中的E627 K取代。然而，具有单个PB 2-E627 K突变的禽流感病毒的聚合酶活性仍然低于季节性人流感病毒，这意味着禽流感病毒除了PB 2 - 627 K之外还需要聚合酶突变来适应人类。在这里，我们使用了一个数据库搜索H5 N1进化枝2.2.1病毒序列与PB 2 - 627 K突变，以确定其他聚合酶适应突变，已被选定在感染的患者。发现的几种突变与PB 2 - 627 K协同作用，增加了人气道上皮细胞和小鼠肺中的病毒生长。这些突变发生在聚合酶复合物的多个结构域中，而不是PB 2 -627结构域，突出了禽流感病毒复杂的禽-人适应途径。因此，H5 N1病毒可以快速获得多个聚合酶突变，这些突变在感染患者中与PB 2 - 627 K协同作用，以实现最佳的人类适应性。H5 N1亚型禽流感病毒是一种散发性传播的病毒，具有较高的致死率（>60%），对全球健康构成严重威胁。特别是，全球最近的人类H5 N1感染病例中有63%是在埃及报告的，埃及现在被认为是H5 N1病毒演变的热点。H5 N1进化枝2.2.1病毒是埃及特有的，可能具有从禽类宿主到人类宿主的最大进化潜力。在这里，使用全面的数据库方法，我们确定了各种新的聚合酶突变的进化枝2.2.1病毒株，从患者中分离，使增强病毒复制在人类气道上皮细胞和小鼠肺。有趣的是，所鉴定的突变与PB 2-E627 K突变（最知名的人类适应性突变）协同作用，使人类宿主中的病毒复制进一步增加。这些结果提供了关于在感染患者中选择的AI病毒的聚合酶特征的第一个广谱数据，也为AI病毒的人类适应机制提供了新的见解。
A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation. Avian influenza (AI) virus H5N1 subtype strains have been sporadically transmitted to humans with high mortality (>60%), presenting a serious global health threat. In particular, 63% of recent human H5N1 infection cases worldwide have been reported in Egypt, which is now regarded as a hot spot for H5N1 virus evolution. H5N1 clade 2.2.1 viruses are unique to Egypt and probably have the greatest evolutionary potential for adaptation from avian to human hosts. Here, using a comprehensive database approach, we identified various novel polymerase mutations in clade 2.2.1 virus strains, isolated from patients, that enabled enhanced viral replication in both human airway epithelial cells and mouse lungs. Interestingly, the mutations identified acted cooperatively with the PB2-E627K mutation, the most well-known human adaptation mutation, to produce a further increase in viral replication in human hosts. These results provide the first broad-spectrum data on the polymerase characteristics of AI viruses that have been selected in infected patients, and also give new insight into the human adaptation mechanisms of AI viruses.