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

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-BP-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Longatti, Andrea; Boyd, Bryan; Chisari, Francis V (2015) Virion-independent transfer of replication-competent hepatitis C virus RNA between permissive cells. J Virol 89:2956-61
Kell, Alison M; Gale Jr, Michael (2015) RIG-I in RNA virus recognition. Virology 479-480:110-21
Horner, Stacy M; Wilkins, Courtney; Badil, Samantha et al. (2015) Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking. PLoS One 10:e0117963
Chakrabarti, Arindam; Banerjee, Shuvojit; Franchi, Luigi et al. (2015) RNase L activates the NLRP3 inflammasome during viral infections. Cell Host Microbe 17:466-77
Kell, Alison; Stoddard, Mark; Li, Hui et al. (2015) Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length. J Virol 89:11056-68
Errett, John S; Gale, Michael (2015) Emerging complexity and new roles for the RIG-I-like receptors in innate antiviral immunity. Virol Sin 30:163-73
Negash, Amina A; Gale Jr, Michael (2015) Hepatitis regulation by the inflammasome signaling pathway. Immunol Rev 265:143-55
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
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

Showing the most recent 10 out of 28 publications