Grass Carp Reovirus Nonstructural Proteins Avoid Host Antiviral Immune Response by Targeting the RLR Signaling Pathway

• Published in: The Journal of immunology (1950) Vol. 208; no. 3; pp. 707 - 719
• Main Authors: Zhang, Jie, Man Wu, Xiao, Fang, Qin, Bi, Yong Hong, Nie, Pin, Chang, Ming Xian
• Format: Journal Article
• Language: English
• Published: United States 01-02-2022
• Subjects: Animals; Carps - virology; Cells, Cultured; DEAD-box RNA Helicases - metabolism; Fish Diseases - immunology; Fish Diseases - virology; Immune Evasion - immunology; Interferon Regulatory Factors - metabolism; Interferons - immunology; Protein Serine-Threonine Kinases - metabolism; Reoviridae - immunology; Reoviridae Infections - immunology; Reoviridae Infections - pathology; Reoviridae Infections - veterinary; TNF Receptor-Associated Factor 3 - metabolism; Viral Nonstructural Proteins - immunology; Virus Replication - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2100723

Grass carp reovirus (GCRV) is a highly virulent RNA virus that mainly infects grass carp and causes hemorrhagic disease. The roles of nonstructural proteins NS38 and NS80 of GCRV-873 in the viral replication cycle and viral inclusion bodies have been established. However, the strategies that NS38 and NS80 used to avoid host antiviral immune response are still unknown. In this study, we report the negative regulations of NS38 and NS80 on the RIG-I-like receptors (RLRs) antiviral signaling pathway and the production of IFNs and IFN-stimulated genes. First, both in the case of overexpression and GCRV infection, NS38 and NS80 inhibited the IFN promoter activation induced by RIG-I, MDA5, MAVS, TBK1, IRF3, and IRF7 and mRNA abundance of key antiviral genes involved in the RLR-mediated signaling. Second, both in the case of overexpression and GCRV infection, NS38 interacted with piscine TBK1 and IRF3, but not with piscine RIG-I, MDA5, MAVS, and TNF receptor-associated factor (TRAF) 3. Whereas NS80 interacted with piscine MAVS, TRAF3, and TBK1, but not with piscine RIG-I, MDA5, and IRF3. Finally, both in the case of overexpression and GCRV infection, NS38 inhibited the formation of the TBK1-IRF3 complex, but NS80 inhibited the formation of the TBK1-TRAF3 complex. Most importantly, NS38 and NS80 could hijack piscine TBK1 and IRF3 into the cytoplasmic viral inclusion bodies and inhibit the translocation of IRF3 into the nucleus. Collectively, all of these data demonstrate that GCRV nonstructural proteins can avoid host antiviral immune response by targeting the RLR signaling pathway, which prevents IFN-stimulated gene production and facilitates GCRV replication.