Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-food Safety and Quality, Ministry of Agriculture of China (26116120), Yangzhou University, Yangzhou, China.
Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-food Safety and Quality, Ministry of Agriculture of China (26116120), Yangzhou University, Yangzhou, China.
Antiviral Res. 2023 Jul;215:105637. doi: 10.1016/j.antiviral.2023.105637. Epub 2023 May 18.
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.
新兴证据表明，长非编码 RNA（lncRNA）在调节基因表达中起着关键作用。然而，流感病毒（IAV）与宿主 lncRNA 相互作用的功能意义和机制仍不清楚。在这里，我们鉴定了一种功能性 lncRNA，LncRNA#61，作为一种广谱抗 IAV 因子。不同亚型的 IAV，包括人 H1N1 病毒和禽 H5N1 和 H7N9 病毒，都会强烈上调 LncRNA#61 的表达。此外，富含核的 LncRNA#61 在 IAV 感染后很快从核内转移到细胞质。强制表达 LncRNA#61 可显著抑制各种亚型的 IAV 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，敲低 LncRNA#61 的表达会显著促进病毒的复制。更重要的是，脂质纳米颗粒（LNP）包裹的 LncRNA#61 策略在抑制小鼠体内病毒复制方面表现出良好的性能。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。在机制上，LncRNA#61 的四个长环臂主要介导其广谱抗病毒作用，并有助于其抑制病毒聚合酶活性和关键聚合酶成分的核聚集。因此，我们将 LncRNA#61 定义为一种潜在的广谱抗 IAV 因子。我们的研究进一步扩展了我们对 lncRNA 惊人的、意料之外的生物学及其与 IAV 密切相互作用的理解，为开发针对宿主 lncRNA 的新型广谱抗 IAV 治疗方法提供了有价值的线索。
