Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells.
Toll-like receptor-3 (TLR3) senses double-stranded RNA, initiating signaling that activates NF-kappaB and interferon regulatory factor 3 (IRF-3), thereby inducing the synthesis of proinflammatory cytokines, type I interferons, and numerous interferon-stimulated genes (ISGs). This pathway has not been extensively investigated in human hepatocytes, and its role in sensing and protecting against hepatitis virus infections is uncertain. We show here that primary human hepatocytes express TLR3 and robustly upregulate ISGs upon poly(I.C) stimulation. We also show that TLR3 senses hepatitis C virus (HCV) infection when expressed in permissive hepatoma cells, acting independently of retinoic acid-inducible gene I and inducing IRF-3 activation and the synthesis of ISGs that restrict virus replication. In turn, HCV infection reduces the abundance of TRIF, an essential TLR3 adaptor, and impairs poly(I.C)-induced signaling. The induction and disruption of TLR3 signaling by HCV may be important factors in determining the outcome of infection and the ability of HCV to establish persistent infections.
Wang
Nan
N
Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Liang
Yuqiong
Y
Devaraj
Santhana
S
Wang
Jie
J
Lemon
Stanley M
SM
Li
Kui
K
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D010641:Phenotype; D012330:RNA, Double-Stranded / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism / Q000502:physiology*; D014709:Vero Cells
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases