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The retinoic acid-inducible gene I (RIG-I) receptor senses cytoplasmic viral RNA and activates type I interferons (IFN-I) and downstream antiviral immune responses. How RIG-I binds to viral RNA and how its activation is regulated remains unclear. Here, using IFI16 knockout cells and p204-deficient mice, we demonstrate that the DNA sensor IFI16 enhances IFN-I production to inhibit influenza A virus (IAV) replication. IFI16 positively upregulates RIG-I transcription through direct binding to and recruitment of RNA polymerase II to the RIG-I promoter. IFI16 also binds to influenza viral RNA via its HINa domain and to RIG-I protein with its PYRIN domain, thus promoting IAV-induced K63-linked polyubiquitination and RIG-I activation. Our work demonstrates that IFI16 is a positive regulator of RIG-I signalling during influenza virus infection, highlighting its role in the RIG-I-like-receptor-mediated innate immune response to IAV and other RNA viruses, and suggesting its possible exploitation to modulate the antiviral response. IFI16 enhances the type I IFN response to inhibit influenza virus replication by two mechanisms: it directly binds viral RNA to promote RIG-I activation and upregulates RIG-I expression via recruiting RNA polymerase II and binding to the RIG-I promoter.
Zhimin Jiang; Fanhua Wei; Yuying Zhang; Tong Wang; Weihua Gao; Shufang Yu; Honglei Sun; Juan Pu; Yipeng Sun; Mingyang Wang; Qi Tong; Chengjiang Gao; Kin-Chow Chang; Jinhua Liu. IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection. Nature Microbiology 2021, 6, 932 -945.
AMA StyleZhimin Jiang, Fanhua Wei, Yuying Zhang, Tong Wang, Weihua Gao, Shufang Yu, Honglei Sun, Juan Pu, Yipeng Sun, Mingyang Wang, Qi Tong, Chengjiang Gao, Kin-Chow Chang, Jinhua Liu. IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection. Nature Microbiology. 2021; 6 (7):932-945.
Chicago/Turabian StyleZhimin Jiang; Fanhua Wei; Yuying Zhang; Tong Wang; Weihua Gao; Shufang Yu; Honglei Sun; Juan Pu; Yipeng Sun; Mingyang Wang; Qi Tong; Chengjiang Gao; Kin-Chow Chang; Jinhua Liu. 2021. "IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection." Nature Microbiology 6, no. 7: 932-945.
Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans.
Tong Wang; Fanhua Wei; Jinhua Liu. Emerging Role of Mucosal Vaccine in Preventing Infection with Avian Influenza A Viruses. Viruses 2020, 12, 862 .
AMA StyleTong Wang, Fanhua Wei, Jinhua Liu. Emerging Role of Mucosal Vaccine in Preventing Infection with Avian Influenza A Viruses. Viruses. 2020; 12 (8):862.
Chicago/Turabian StyleTong Wang; Fanhua Wei; Jinhua Liu. 2020. "Emerging Role of Mucosal Vaccine in Preventing Infection with Avian Influenza A Viruses." Viruses 12, no. 8: 862.
The type I interferons (IFNs) represent the first line of host defense against influenza virus infection, and the precisely control of the type I IFNs responses is a central event of the immune defense against influenza viral infection. Influenza viruses are one of the leading causes of respiratory tract infections in human and are responsible for seasonal epidemics and occasional pandemics, leading to a serious threat to global human health due to their antigenic variation and interspecies transmission. Although the host cells have evolved sophisticated antiviral mechanisms based on sensing influenza viral products and triggering of signalling cascades resulting in secretion of the type I IFNs (IFN-α/β), influenza viruses have developed many strategies to counteract this mechanism and circumvent the type I IFNs responses, for example, by inducing host shut-off, or by regulating the polyubiquitination of viral and host proteins. This review will summarise the current knowledge of how the host cells recognise influenza viruses to induce the type I IFNs responses and the strategies that influenza viruses exploited to evade the type I IFNs signalling pathways, which will be helpful for the development of antivirals and vaccines.
Chengye Li; Tong Wang; Yuying Zhang; Fanhua Wei. Evasion mechanisms of the type I interferons responses by influenza A virus. Critical Reviews in Microbiology 2020, 46, 1 -13.
AMA StyleChengye Li, Tong Wang, Yuying Zhang, Fanhua Wei. Evasion mechanisms of the type I interferons responses by influenza A virus. Critical Reviews in Microbiology. 2020; 46 (4):1-13.
Chicago/Turabian StyleChengye Li; Tong Wang; Yuying Zhang; Fanhua Wei. 2020. "Evasion mechanisms of the type I interferons responses by influenza A virus." Critical Reviews in Microbiology 46, no. 4: 1-13.
Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity. The innate immune system is the first line of host defense against microbial infection, while viruses develop several strategies to evade the host defense. It is of great significance to explore the mechanism by which viruses to evade the antiviral host defense. Previous studies have found that progranulin (PGRN) plays an important role in a variety of physiologic and disease processes. Here, we demonstrated that PGRN induced by influenza virus negatively regulated type I IFN production by inhibiting the activation of NF-κB and IRF3 signaling. We further showed that PGRN directly interacted with NEMO via its Grn CDE domains and recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO. Macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our findings highlight a new strategy whereby influenza virus to evade type I IFN-mediated antiviral immune response and also provide insights into the functions and crosstalk of PGRN in innate immunity.
Fanhua Wei; Zhimin Jiang; Honglei Sun; Juan Pu; Yipeng Sun; Mingyang Wang; Qi Tong; Yuhai Bi; Xiaojing Ma; George Fu Gao; Jinhua Liu. Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLOS Pathogens 2019, 15, e1008062 .
AMA StyleFanhua Wei, Zhimin Jiang, Honglei Sun, Juan Pu, Yipeng Sun, Mingyang Wang, Qi Tong, Yuhai Bi, Xiaojing Ma, George Fu Gao, Jinhua Liu. Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLOS Pathogens. 2019; 15 (10):e1008062.
Chicago/Turabian StyleFanhua Wei; Zhimin Jiang; Honglei Sun; Juan Pu; Yipeng Sun; Mingyang Wang; Qi Tong; Yuhai Bi; Xiaojing Ma; George Fu Gao; Jinhua Liu. 2019. "Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling." PLOS Pathogens 15, no. 10: e1008062.