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 sensing and limiting intracellular HCV RNA replication, the role of TLR3 signaling in cellular recognition and control of HCV infection remains unknown, 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 by itself and/or in synergy with other antiviral signaling mechanisms. We propose the following aims: 1. Determine whether TLR3 signaling contributes to cellular control of HCV replication. 2. Determine whether HCV replication activates TLR3 signaling pathway in hepatocytes. 3. Characterize the mechanisms of TLR3 signaling in hepatocytes. 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 benefit the design of new therapeutic interventions for HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069285-05
Application #
7772297
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2007-03-15
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$251,538
Indirect Cost
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
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