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Journal of Virology, October 2009, p. 9824-9834, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01125-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells {triangledown} ,{dagger}

Nan Wang,1,2,{ddagger} Yuqiong Liang,1,{ddagger} Santhana Devaraj,1 Jie Wang,2 Stanley M. Lemon,1* and Kui Li1,2*

Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555,1 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 381632

Received 2 June 2009/ Accepted 14 July 2009

Toll-like receptor-3 (TLR3) senses double-stranded RNA, initiating signaling that activates NF-{kappa}B 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.

* Corresponding author. Mailing address for Kui Li: 858 Madison Ave., 401B Molecular Sciences Building, Memphis, TN 38163. Phone: (901) 448-2571. Fax: (901) 448-7360. E-mail: kli1{at}utmem.edu. Mailing address for Stanley M. Lemon: 6.200 Galveston National Laboratory, 301 University Blvd., Galveston, TX 77555-0610. Phone: (409) 266-6500. Fax: (409) 266-6810. E-mail: smlemon{at}utmb.edu

{triangledown} Published ahead of print on 22 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} N. Wang and Y. Liang contributed equally to this work.

Journal of Virology, October 2009, p. 9824-9834, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01125-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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