Abstract

Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis C virus (HCV), a positive strand RNA virus that frequently establishes persistent infections leading to chronic hepatitis, cirrhosis and liver cancer. However, little is known about how hepatocytes sense HCV infection and initiate protective responses. We have recently shown that non-neoplastic PH5CH8 hepatocytes contain two distinct antiviral signaling pathways, Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I), to recognize viral double-stranded (ds) RNA and lead to subsequent interferon antiviral response. Our long-term goal is to elucidate the role of these signaling pathways in hepatocellular control of HCV infection. While RIG-I signaling was recently shown to contribute to sense intracellular HCV RNA replication, the role of TLR3 signaling in recognition and control of HCV infection remains to be determined, as previous investigations were all conducted in hepatoma Huh7 cells which lack a functional TLR3 pathway. We hypothesize that TLR3 signaling is an important antiviral mechanism of hepatocytes, and contributes to host defenses against HCV. We propose three aims for this application: (1) Determine the subcellular localization of TLR3 and the mechanism of TLR3 signaling in hepatocytes where it is initiated and to what extent it cross-talks with the RIG-I pathway. (2) Determine whether structured HCV RNA and HCV infection activate TLR3 signaling pathway in TLR3 reconstituted Huh cells and whether TLR3 is associated with HCV replication complex in cells supporting HCV replication. (3) Determine whether TLR3 signaling contributes to hepatocellular control of HCV replication. This proposed research shall advance our knowledge regarding virus-host interactions in hepatitis C pathogenesis and the role of innate immunity in controlling HCV infection, which would potentially benefit the design of new therapeutic interventions for HCV infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI069285-03
Application #
7680814
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2007-03-15
Project End
2012-02-28
Budget Start
2008-07-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$128,837
Indirect Cost

  Institution

Name
University of Tennessee Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163

  Publications

Kumthip, Kattareeya; Yang, Darong; Li, Nan L et al. (2017) Pivotal role for the ESCRT-II complex subunit EAP30/SNF8 in IRF3-dependent innate antiviral defense. PLoS Pathog 13:e1006713
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2016) (-)-Epigallocatechin-3-Gallate Enhances Hepatitis C Virus Double-Stranded RNA Intermediates-Triggered Innate Immune Responses in Hepatocytes. Sci Rep 6:21595
Wei, Dahai; Li, Nan L; Zeng, Yanli et al. (2016) The Molecular Chaperone GRP78 Contributes to Toll-like Receptor 3-mediated Innate Immune Response to Hepatitis C Virus in Hepatocytes. J Biol Chem 291:12294-309
Liu, Baoming; Li, Nan L; Shen, Yang et al. (2016) The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis. J Virol 90:4369-4382
Yang, Chuan He; Li, Kui; Pfeffer, Susan R et al. (2015) The Type I IFN-Induced miRNA, miR-21. Pharmaceuticals (Basel) 8:836-47
Brownell, Jessica; Bruckner, Jacob; Wagoner, Jessica et al. (2014) Direct, interferon-independent activation of the CXCL10 promoter by NF-?B and interferon regulatory factor 3 during hepatitis C virus infection. J Virol 88:1582-90
Wang, Dang; Fang, Liurong; Wei, Dahai et al. (2014) Hepatitis A virus 3C protease cleaves NEMO to impair induction of beta interferon. J Virol 88:10252-8
Lester, Sandra N; Li, Kui (2014) Toll-like receptors in antiviral innate immunity. J Mol Biol 426:1246-64
Liu, Baoming; Li, Nan L; Wang, Jie et al. (2014) Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus. J Virol 88:13821-35
Pfeffer, Lawrence M; Li, Kui; Fleckenstein, Jaquelyn F et al. (2014) An interferon response gene signature is associated with the therapeutic response of hepatitis C patients. PLoS One 9:e104202

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