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Although there is no proven medication for hepatitis E, pegylated interferon\u2010\u03b1 (IFN\u2010\u03b1) has been used as off\u2010label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN\u2010\u03b1 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\u2013host 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\u2010\u03b1 was the sole humoral factor inhibiting HEV replication. IFN\u2010\u03b1 treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti\u2010HEV effects<jats:italic>in vitro<\/jats:italic>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\u2010STAT 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.<\/jats:p>","DOI":"10.1111\/jvh.12491","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T11:22:42Z","timestamp":1448968962000},"page":"294-304","source":"Crossref","is-referenced-by-count":37,"title":["Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection"],"prefix":"10.1111","volume":"23","author":[{"given":"X.","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC\u2010University Medical Center and Postgraduate School Molecular Medicine Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC\u2010University Medical Center and Postgraduate School Molecular Medicine Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC\u2010University Medical Center and Postgraduate School Molecular Medicine Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Watashi","sequence":"additional","affiliation":[{"name":"Department of Virology II National Institute of Infectious Diseases Shinjuku\u2010ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC\u2010University Medical Center and Postgraduate School Molecular Medicine Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Sprengers","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC\u2010University Medical Center and Postgraduate School Molecular Medicine Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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