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Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells.

ABSTRACT: 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.

SUBMITTER: Wang N

PROVIDER: S-EPMC2747996 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells.

Wang Nan N Liang Yuqiong Y Devaraj Santhana S Wang Jie J Lemon Stanley M SM Li Kui K

Journal of virology 20090722 19

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 ro ...[more]

PMID: 19625408

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Project description:BackgroundInterferon and nucleos(t)ide analogues are current therapeutic treatments for chronic Hepatitis B virus (HBV) infection with the limitations of a functional cure. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid, known for its antiviral and hepatoprotective activities. However, its anti-HBV activity is unexplored.MethodsIn the present study, the anti-hepatitis B activity of chrysin was investigated using the in vitro experimental cell culture model, HepG2 cells. In silico studies were performed where chrysin and lamivudine (used here as a positive control) were docked with high mobility group box 1 protein (HMGB1). For the in vitro studies, wild type HBV genome construct (pHBV 1.3X) was transiently transfected in HepG2. In culture supernatant samples, HBV surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) were measured by enzyme-linked immunosorbent assay (ELISA). Secreted HBV DNA and intracellular covalently closed circular DNA (cccDNA) were measured by SYBR green real-time PCR. The 3D crystal structure of HMGB1 (1AAB) protein was developed and docked with the chrysin and lamivudine. In silico drug-likeness, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of finest ligands were performed by using SwissADME and admetSAR web servers.ResultsData showed that chrysin significantly decreases HBeAg, HBsAg secretion, supernatant HBV DNA and cccDNA, in a dose dependent manner. The docking studies demonstrated HMGB1 as an important target for chrysin as compared to lamivudine. Chrysin revealed high binding affinity and formed a firm kissing complex with HMGB1 (∆G = - 5.7 kcal/mol), as compared to lamivudine (∆G = - 4.3 kcal/mol), which might be responsible for its antiviral activity.ConclusionsThe outcome of our study establishes chrysin as a new antiviral against HBV infection. However, using chrysin to treat chronic HBV disease needs further endorsement and optimization by in vivo studies in animal models.

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Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells.

Publications

Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells.

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