title: Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.
abstract: Innate immunity controls pathogen replication and spread. Yet, certain pathogens, such as Hepatitis C Virus (HCV), escape immune elimination and establish persistent infections that promote chronic inflammation and related diseases. Whereas HCV regulatory proteins that attenuate antiviral responses are known, those that promote inflammation and liver injury remain to be identified. Here, we show that transient expression of HCV RNA-dependent RNA polymerase (RdRp), NS5B, in mouse liver and human hepatocytes results in production of small RNA species that activate innate immune signaling via TBK1-IRF3 and NF-κB and induce cytokine production, including type I interferons (IFN) and IL-6. NS5B-expression also results in liver damage.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0723, USA. guannyiy@nhri.org.tw
authors.forename: Guann-Yi
authors.initials: GY
authors.lastname: Yu
authors.forename: Guobin
authors.initials: G
authors.lastname: He
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Tang
authors.forename: Sergei
authors.initials: S
authors.lastname: Grivennikov
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Tsai
authors.forename: Ming-Sian
authors.initials: MS
authors.lastname: Wu
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Hsu
authors.forename: Yu
authors.initials: Y
authors.lastname: Tsai
authors.forename: Lily Hui-Ching
authors.initials: LH
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D015850:Interleukin-6; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C403191:TBK1 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase