State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China.
Shenzhen Key Laboratory of Pathogen and Immunity, State Key Discipline of Infectious Disease, Second Hospital Affiliated with Southern University of Science and Technology, Shenzhen Third People's Hospital, Shenzhen, Guangdong, 518112, China.
Cell Mol Immunol. 2022 Jun;19(6):702-714. doi: 10.1038/s41423-022-00843-8. Epub 2022 Mar 24.
Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can better escape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by which transcriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouse lungs, and patient PBMCs, we showed that genes on the complementary strand ("trans" genes) influenced by TRT were involved in the disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishment increased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 induced TRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT by reducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.
先天免疫在抗病毒方面发挥着关键作用。高度致命的禽流感病毒（AIVs）H5N1、H7N9 和 H5N6 比低致命性的季节性 H1N1 病毒更能逃避宿主先天免疫反应。在这里，我们报告了一种 AIV 感染后通过转录通读（TRT）介导抑制先天免疫的机制。通过使用细胞系、小鼠肺和患者 PBMC，我们表明 TRT 影响的互补链上的基因（“反义”基因）参与了 AIV 感染期间破坏宿主抗病毒反应。反义 TRT 增强了病毒的致死性，而 TRT 消除增加了细胞活力和 STAT1/2 的表达。病毒 NS1 蛋白直接与 SSU72 结合，而 SSU72 的降解诱导了 TRT。SSU72 的过表达减少了 TRT 并减轻了小鼠肺损伤。我们的研究结果表明，AIV 感染通过降低 SSU72 的表达诱导 TRT，从而损害宿主免疫反应，这是一种通过 NS1-SSU72-反义 TRT-STAT1/2 轴起作用的分子机制。因此，恢复 SSU72 的表达可能是预防 AIV 大流行的一种潜在策略。
