甲型流感病毒基因组的结构。,Nature Microbiology

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甲型流感病毒基因组的结构。
Nature Microbiology ( IF 20.5 ) Pub Date : 2019-07-22 , DOI: 10.1038/s41564-019-0513-7
Bernadeta Dadonaite ₁ , Brad Gilbertson ₂ , Michael L Knight ₁ , Sanja Trifkovic ₂ , Steven Rockman _{2,

3} , Alain Laederach ₄ , Lorena E Brown ₂ , Ervin Fodor ₁ , David L V Bauer ₁

Affiliation

甲型流感病毒（IAV）对人类健康构成重大威胁。IAV基因组由包含在单独的病毒核糖核蛋白（vRNP）复合物中的八个单链病毒RNA片段组成，这些复合物一起包装成一个病毒颗粒。病毒RNA的结构被认为在将不同的vRNPs组装成萌芽的病毒体1-8并指导IAVs9之间的重配中发挥了作用。已建立的人类IAV与动物水库中所携带的IAV之间的重排会导致大流行性流感病毒株的出现，而该人群在人群中几乎没有预先存在的免疫力10,11。尽管先前的研究已经揭示了vRNP中蛋白质的整体结构，使用常规结构方法表征病毒RNA结构的方法因分辨率有限和无法解析动态成分而受到阻碍[12,13]。在这里，我们采用多种高通量测序方法来生成IAV基因组的全局高分辨率结构。我们显示，不同的IAV基因组片段获得不同的RNA构象，并在流感病毒粒子内部形成段内和段间RNA相互作用。我们使用IAV基因组结构的详细图谱来提供直接证据，证明在不同IAV株之间重配期间，节间RNA相互作用如何驱动vRNP共分离。此处介绍的工作既是开发改良疫苗株的路线图，也是建立“风险评估”框架的路线图。

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The structure of the influenza A virus genome.

Influenza A viruses (IAVs) constitute a major threat to human health. The IAV genome consists of eight single-stranded viral RNA segments contained in separate viral ribonucleoprotein (vRNP) complexes that are packaged together into a single virus particle. The structure of viral RNA is believed to play a role in assembling the different vRNPs into budding virions1-8 and in directing reassortment between IAVs9. Reassortment between established human IAVs and IAVs harboured in the animal reservoir can lead to the emergence of pandemic influenza strains to which there is little pre-existing immunity in the human population10,11. While previous studies have revealed the overall organization of the proteins within vRNPs, characterization of viral RNA structure using conventional structural methods is hampered by limited resolution and an inability to resolve dynamic components12,13. Here, we employ multiple high-throughput sequencing approaches to generate a global high-resolution structure of the IAV genome. We show that different IAV genome segments acquire distinct RNA conformations and form both intra- and intersegment RNA interactions inside influenza virions. We use our detailed map of IAV genome structure to provide direct evidence for how intersegment RNA interactions drive vRNP cosegregation during reassortment between different IAV strains. The work presented here is a roadmap both for the development of improved vaccine strains and for the creation of a framework to 'risk assess' reassortment potential to better predict the emergence of new pandemic influenza strains.

更新日期：2019-07-22

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