Project 1 comprises a component of our Hepatitis C virus Cooperative Research Center (HC CRC) U19 application. The focus of Project 1 is to understand the molecular mechanisms by which HCV is recognized by the host cell as a foreign pathogen to trigger immunity against infection, and to learn how HCV evades these processes to mediate infection outcome among clinical cases of HCV. HCV is a hepatotropic virus that mediates a persistent infection and chronic liver disease in millions of people worldwide. HCV persistence is associated with viral strategies to evade innate immune defenses and ap interferon (IFN) immune actions that normally limit Infection. We have identified HCV genome RNA and the cellular RIG-I protein as the viral pathogen-associated molecular pattern (PAMP) and host pathogen recognition receptor that Interact to trigger the expression of RIG-l-responsive genes that serve as immune effectors to control innate immunity and HCV infection. We have found that HCV can disrupt innate immune signaling via the actions of the viral NS3/4A protease, thus providing an evasion strategy that allows HCV to persist. We hypothesize that viral PAMP signaling and gene expression mediated through the RIG-I pathway are critical determinants controlling hepatic immunity and the outcome of HCV infection. Our studies are therefore deigned 1) Define the structure-function relationship of viral PAMP recognition by RIG-I among clinical isolates of HCV, 2) Identify the RIG-l-responsive genes of the liver that regulate HCV infection, and 3) Determine the function of NS3/4A to regulate the RIG-I pathway among clinical cases of HCV infected with different viral genotypes. Our studies are linked with the U19 Clinical Core, and Projects 2 and 3 to feature translational approaches aimed at defining the virus-host interface that controls hepatic innate immunity and HCV infection.

Public Health Relevance

Hepatitis C virus causes a chronic infection In nearly 200 million people. Our studies aim to understand how HCV triggers and controls immunity to infection. Results from this work will reveal novel interactions of the virus-host interface of HCV infection within the liver, the target organ of this virus, thus providing new opportunities for the design of therapeutic strategies to limit HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI088778-05
Application #
8648991
Study Section
Special Emphasis Panel (ZAI1-BP-M)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$262,683
Indirect Cost
$40,662
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wieland, Stefan; Makowska, Zuzanna; Campana, Benedetta et al. (2014) Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver. Hepatology 59:2121-30
McFarland, Adelle P; Horner, Stacy M; Jarret, Abigail et al. (2014) The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat Immunol 15:72-9
Ireton, ReneƩ C; Gale Jr, Michael (2014) Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res 108:156-64
Wieland, S F; Takahashi, K; Boyd, B et al. (2014) Human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus-infected cells in vitro. J Virol 88:752-7
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
Horner, Stacy M; Gale Jr, Michael (2013) Regulation of hepatic innate immunity by hepatitis C virus. Nat Med 19:879-88
Ireton, Renee C; Gale Jr, Michael (2013) Systems biology analyses to define host responses to HCV infection and therapy. Curr Top Microbiol Immunol 363:143-67
Negash, Amina A; Ramos, Hilario J; Crochet, Nanette et al. (2013) IL-1? production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog 9:e1003330
Patel, Maulik R; Loo, Yueh-Ming; Horner, Stacy M et al. (2012) Convergent evolution of escape from hepaciviral antagonism in primates. PLoS Biol 10:e1001282
Loo, Yueh-Ming; Gale Jr, Michael (2011) Immune signaling by RIG-I-like receptors. Immunity 34:680-92

Showing the most recent 10 out of 13 publications