Impaired host response and HCV disturbance of type I/III IFN signaling are closely associated with non-response to IFN-based anti-HCV treatment

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590960
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OOKA Shinya 東京医科歯科大学, 医歯(薬)学総合研究科, 特任准教授 (90361691)
• Co-Investigator(Kenkyū-buntansha): ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692) ; WATANABE Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Co-Investigator(Renkei-kenkyūsha): SAKAMOTO Naoya 北海道大学, 医学研究科, 教授 (10334418)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: ＨＣＶ / インターフェロン / ＮＳ4Ｂ / ＩＬ28Ｂ

Outline of Final Research Achievements

HCV infection blocks cellular IFN-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, we found NS4B protein strongly blocks IFN-β production signaling mediated by RIG-I. IFN-β promoter reporter assay showed that IFN-β promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-β activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Therefore, NS4B suppresses RIG-I-mediated IFN-β production signaling through a direct protein interaction with STING. Moreover, we reported over-expression of IL6, which is inhibitory molecule of type I/III IFN signaling, and IL28B (type III IFN) SNPs were closely associated with non-response to IFN-based anti-HCV therapy.

Free Research Field

消化器内科