Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72

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 suppressi...

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Bibliographic Details
Published in:Cellular & molecular immunology 2022-06, Vol.19 (6), p.702-714
Main Authors: Zhao, Yan, Huang, Fengming, Zou, Zhen, Bi, Yuhai, Yang, Yang, Zhang, Cong, Liu, Qiang, Shang, Daozhen, Yan, Yiwu, Ju, Xiangwu, Mei, Song, Xie, Peng, Li, Xiao, Tian, Mingyao, Tan, Shuguang, Lu, Huijun, Han, Zongsheng, Liu, Kangtai, Zhang, Yuqing, Liang, Junbo, Liang, Zhu, Zhang, Qingchao, Chang, Jiahui, Liu, William J., Feng, Cong, Li, Tanshi, Zhang, Michael Q., Wang, Xiaoyue, Gao, George F., Liu, Yingxia, Jin, Ningyi, Jiang, Chengyu
Format: Article
Language:English
Subjects:
631/250/2161
631/250/254
Antibodies
Avian flu
Biomedical and Life Sciences
Biomedicine
Cell lines
Cell viability
Immune response
Immunology
Infections
Influenza
Innate immunity
Lethality
Medical Microbiology
Microbiology
NS1 protein
Orthomyxoviridae
Stat1 protein
Vaccine
Virulence
Viruses
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Summary: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.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-022-00843-8