title: Hepatitis C virus impairs TLR3 signaling and inhibits IFN-λ 1 expression in human hepatoma cell line.
abstract: Toll-like receptor 3 (TLR3) activation plays an important role in the innate immune responses to viral infections. We show here that the activation of TLR3 signaling pathway by poly I:C, a synthetic mimic of dsRNA, could induce high-level expression of interferon (IFN)-λ1 in a hepatoma cell line. The induced IFN-λ1 contributed to poly I:C-mediated inhibition of hepatitis C virus (HCV) Japanese fulminant hepatitis-1 (JFH-1) replication in Huh7 cells. This inhibitory effect of poly I:C on HCV replication, however, was compromised by HCV infection of Huh7 cells. Investigation of the mechanisms showed that HCV infection suppressed the expression of poly I:C-induced IFN-λ1 and IFN-stimulated genes [IFN-stimulated gene 56 (ISG-56), myxovirus resistance A (MxA) and 2'-5'-oligoadenylate synthetase 1 (OAS-1))], the key antiviral elements in IFN signaling pathway. Among the HCV nonstructural (NS) proteins tested, NS3/4A, NS5A and NS5B had the ability to inhibit poly I:C-induced IFN-λ1 expression in Huh7 cells. These observations provide the experimental evidence that HCV and its proteins impair TLR3 signaling and inhibit intracellular IFN-λ1/ISG expression in a hepatoma cell line, which may account for HCV persistence in the liver.
authors.affiliation: 1The Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, People's Republic of China.
authors.forename: Yizhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Jieliang
authors.initials: J
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Thomas
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Ho
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000821:virology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology* / Q000821:virology; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology; D000095022:Interferon Lambda
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D048868:Adaptor Proteins, Signal Transducing; D007372:Interferons; D007378:Interleukins; D064547:Myxovirus Resistance Proteins; D011070:Poly I-C; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; C484290:IFIT1 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human; C495344:TLR3 protein, human; C475085:OAS1 protein, human
keywords: Hepatitis C virus; IFN-stimulated genes; Toll-like receptor 3; interferon-λ; poly I:C