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

Zhao，Yan1; Huang，Fengming1; Zou，Zhen1; Bi，Yuhai2,3; Yang，Yang2; Zhang，Cong1,4; Liu，Qiang1; Shang，Daozhen1; Yan，Yiwu1; Ju，Xiangwu1; Mei，Song1; Xie，Peng5; Li，Xiao6; Tian，Mingyao6; Tan，Shuguang2,3; Lu，Huijun6; Han，Zongsheng1; Liu，Kangtai1; Zhang，Yuqing1,7; Liang，Junbo8; Liang，Zhu1; Zhang，Qingchao1; Chang，Jiahui1; Liu，William J.2,9; Feng，Cong10; Li，Tanshi10; Zhang，Michael Q.5,11; Wang，Xiaoyue8; Gao，George F.2,3; Liu，Yingxia2; Jin，Ningyi6; Jiang，Chengyu1

2022

10.1038/s41423-022-00843-8

Cellular & Molecular Immunology   影响因子和分区

1672-7681

2042-0226

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.

AIV infection Immune escape NS1 SSU72 TRT

SCI

英语

通讯

National Natural Science Foundation of China (NSFC)[81788101,31870163,32100104] ; CAMS Innovation Fund for Medical Sciences[2021-I2M-1-022] ; Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDB29010102] ; CAS Southest Asia Biodiversity Research Institute[151C53KYSB20210023] ; Beijing Natural Science Foundation[L192007] ; State Key Laboratory Special Fund[2060204] ; NSFC Outstanding Young Scholars[31822055] ; Youth Innovation Promotion Association of the CAS[2017122,"Y2021034"] ; Overseas Expertise Introduction Center for Discipline Innovation ("111 Center")[BP0820029]

Immunology

Immunology

WOS:000780300100003

CHIN SOCIETY IMMUNOLOGY

2-s2.0-85127479223

Scopus

1.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
2.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
3.CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning (CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID),Chinese Academy of Sciences,Beijing,100101,China
4.School of Life Science,University of Science and Technology of China,Hefei,Anhui,230027,China
5.Department of Automation,Tsinghua University,Beijing,100084,China
6.Genetic Engineering Laboratory,Institute of Military Veterinary,Academy of Military Medical Sciences,Changchun,Jilin,130062,China
7.State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy,West China Hospital,Sichuan University,Chengdu,Sichuan,610000,China
8.State Key Laboratory of Medical Molecular Biology,Department of Biochemistry and Center for Bioinformatics,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,School of Basic Medicine,Peking Union Medical College,Beijing,100005,China
9.National Institute for Viral Disease Control and Prevention,Chinese Centers for Disease Control and Prevention,Beijing,102206,China
10.Department of Emergency,General Hospital of the PLA,Haidian District,Beijing,100853,China
11.Department of Biological Sciences and Center for Systems Biology,The University of Texas at Dallas,Richardson,United States

Zhao，Yan,Huang，Fengming,Zou，Zhen,et al. Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72[J]. Cellular & Molecular Immunology,2022.

Zhao，Yan.,Huang，Fengming.,Zou，Zhen.,Bi，Yuhai.,Yang，Yang.,...&Jiang，Chengyu.(2022).Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72.Cellular & Molecular Immunology.

Zhao，Yan,et al."Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72".Cellular & Molecular Immunology (2022).