新的证据已经证明了长链非编码RNA(lncRNA)在调节基因表达中的关键作用。然而,甲型流感病毒(IAV)-宿主lncRNA相互作用的功能意义和机制仍然难以捉摸。这里,我们发现了一种功能性的lncRNA,LncRNA#61,作为广泛的抗IAV因子。LncRNA#61被不同亚型的IAV高度上调,包括人类H1N1病毒和禽流感H5N1和H7N9病毒。此外,核富集的LncRNA#61可以在IAV感染后不久从细胞核转移到细胞质。强制LncRNA#61表达显著阻碍各种亚型IAV的病毒复制,包括人H1N1病毒和禽H3N2/N8、H4N6、H5N1、H6N2/N8、H7N9、H8N4、H10N3、H11N2/N6/N9病毒。相反,消除LncRNA#61表达基本上有利于病毒复制。更重要的是,通过脂质纳米颗粒(LNP)包封的策略递送的LncRNA#61在抑制小鼠中的病毒复制中显示出良好的性能。有趣的是,LncRNA#61参与病毒复制周期的多个步骤,包括病毒进入,病毒RNA合成和病毒释放期。机械上,LncRNA#61的四个长环臂主要介导其广泛的抗病毒作用,并有助于其抑制病毒聚合酶活性和关键聚合酶组分的核聚集。因此,我们将LncRNA#61定义为一种潜在的IAV广谱抗病毒因子.我们的研究进一步扩展了我们对lncRNAs惊人和意想不到的生物学以及它们与IAV的密切相互作用的理解。为开发靶向宿主lncRNAs的新型广泛抗IAV疗法提供有价值的线索。
Emerging evidence has demonstrated the critical role of long noncoding RNAs (lncRNAs) in regulating gene expression. However, the functional significance and mechanisms underlying influenza A virus (IAV)-host lncRNA interactions are still elusive. Here, we identified a functional lncRNA, LncRNA#61, as a broad anti-IAV factor. LncRNA#61 is highly upregulated by different subtypes of IAV, including human H1N1 virus and avian H5N1 and H7N9 viruses. Furthermore, nuclear-enriched LncRNA#61 can translocate from the nucleus to the cytoplasm soon after IAV infection. Forced LncRNA#61 expression dramatically impedes viral replication of various subtypes of IAV, including human H1N1 virus and avian H3N2/N8, H4N6, H5N1, H6N2/N8, H7N9, H8N4, H10N3, H11N2/N6/N9 viruses. Conversely, abolishing LncRNA#61 expression substantially favored viral replication. More importantly, LncRNA#61 delivered by the lipid nanoparticle (LNP)-encapsulated strategy shows good performance in restraining viral replication in mice. Interestingly, LncRNA#61 is involved in multiple steps of the viral replication cycle, including virus entry, viral RNA synthesis and the virus release period. Mechanistically, the four long ring arms of LncRNA#61 mainly mediate its broad antiviral effect and contribute to its inhibition of viral polymerase activity and nuclear aggregation of key polymerase components. Therefore, we defined LncRNA#61 as a potential broad-spectrum antiviral factor for IAV. Our study further extends our understanding of the stunning and unanticipated biology of lncRNAs as well as their close interaction with IAV, providing valuable clues for developing novel broad anti-IAV therapeutics targeting host lncRNAs.