title: RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus regardless of interferon production.
abstract: Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti-HEV ISG was further studied. We identified retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti-HEV ISGs. We found that basal expression of RIG-I restricts HEV infection. Pharmacological activation of the RIG-I pathway by its natural ligand 5'-triphosphate RNA potently inhibits HEV replication. Overexpression of RIG-I activates the transcription of a wide range of ISGs. RIG-I also mediates but does not overlap with IFN-α-initiated ISG transcription. Although it is classically recognized that RIG-I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN-independent antiviral mechanism of RIG-I in combating HEV infection. We found that activation of RIG-I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG-I activated two distinct categories of ISGs, one JAK-STAT-dependent and the other JAK-STAT-independent, which coordinately contribute to the anti-HEV activity.
  
  
  
  We identified RIG-I as an important anti-HEV ISG that can be pharmacologically activated; activation of RIG-I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK-STAT cascade of IFN signaling. (Hepatology 2017;65:1823-1839).
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Medical Faculty, Kunming University of Science and Technology, Kunming, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert A
authors.initials: RA
authors.lastname: de Man
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJW
authors.lastname: van der Laan
authors.affiliation: Medical Faculty, Kunming University of Science and Technology, Kunming, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.|INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.|University Toulouse III-Paul Sabatier, Toulouse, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D002478:Cells, Cultured; D000071457:DEAD Box Protein 58 / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D016751:Hepatitis E / Q000235:genetics* / Q000276:immunology; D016752:Hepatitis E virus / Q000235:genetics* / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D014779:Virus Replication / Q000235:genetics* / Q000276:immunology
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58