title: Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection.
abstract: Hepatitis E virus (HEV) represents one of the foremost causes of acute hepatitis globally. Although there is no proven medication for hepatitis E, pegylated interferon-α (IFN-α) has been used as off-label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN-α has been approved for treating chronic hepatitis C (HCV) for decades and the role of interferon signalling has been well studied in HCV infection, this study aimed to comprehensively investigate virus-host interactions in HEV infection with focusing on the IFN signalling, in comparison with HCV infection. A comprehensive screen of human cytokines and chemokines revealed that IFN-α was the sole humoral factor inhibiting HEV replication. IFN-α treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti-HEV effects in vitro and in patients. Surprisingly, blocking the basal IFN pathway by inhibiting JAK1 to phosphorylate STAT1 has resulted in drastic facilitation of HEV, but not HCV infection. Gene silencing of the key components of JAK-STAT cascade of the IFN signalling, including JAK1, STAT1 and interferon regulatory factor 9 (IRF9), stimulated HEV infection. In conclusion, compared to HCV, HEV is less sensitive to IFN treatment. In contrast, the basal IFN cascade could effectively restrict HEV infection. This bears significant implications in management of HEV patients and future therapeutic development.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: P E
authors.initials: PE
authors.lastname: de Ruiter
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: L J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA, Toulouse Cedex 9, France.|INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: N
authors.initials: N
authors.lastname: Kamar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019698:Hepatitis C, Chronic / Q000473:pathology / Q000628:therapy; D016751:Hepatitis E / Q000473:pathology* / Q000628:therapy*; D016752:Hepatitis E virus / Q000276:immunology* / Q000502:physiology; D022781:Hepatocytes / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000627:therapeutic use; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha
keywords: Hepatitis E virus; JAK-STAT cascades; interferon-stimulated genes; interferons