Hepatitis C is characterized histologically by an intense infiltration of immune cells into the liver. This project seeks to understand how HCV infection of hepatocytes leads to induction of chemokines that cause immune cells to home to the liver. When hepatocytes become infected, at least two pattern recognition receptors (PRR), TLRS and RIG-I, sense the HCV RNA pathogen associated nnolecular pattern (PAMP), resulting in activation of innate antiviral and inflammatory responses. Our group was the first to show that both in vitro and in vivo HCV infection is associated with induction of CXCL8, a highly inflammatory chemokine. We have since found that RIG-I sensing of HCV infection causes CXCL8 induction by h/vo major mechanisms: transcriptional activation and mRNA stabilization. The convergence of PRR sensing of HCV infection with inflammatory chemokine induction will be the focus of the proposed studies. Studies by other groups have since found associations of chemokines such as CXCL9 (monokine induced by interferon gamma;Mig), CXCL-10 (interferon-gamma-inducible protein-10;IP-10), and CXCL11 (interferon-Inducible T-cell alpha chemoattractant;l-TAC) with chronic hepatitis C. Moreover, CXCL9-11 signal through CXCR3 and this chemokine receptor is known to be integral in the migration of immune cells including T, dendritic, and NKT cells into the liver. Chemokine induction following HCV infection of a liver cell is therefore central to immune cell trafficking to the liver and induction of an inflammatory response, which contributes to liver damage, and as we have shown, reduced efficacy of interferon therapy. However, there is a paucity of information on how chemokines that cause immune cells to home to the liver are induced during HCV infection. The central hypothesis of this project is that PRR sensing of HCV infection in hepatocytes leads to chemokine recruitment of CXCR3+ immune cells to the liver. To address the hypothesis, we propose 3 Specific Aims that will determine the relative contribution of TLR-3 and RIG-I in chemokine induction, determine how cellular sensing of HCV infection results in stabilization of chemokine mRNAs, and evaluate chemokines as a link between innate and adaptive immune responses in terms of immune cell chemotaxis and hepatocyte:immune cell interactions during HCV infection. The proposed studies will provide basic insight into PRR induction of an inflammatory response, the roles of chemokines in hepatic inflammation and disease, and links between innate and adaptive immunity.

Public Health Relevance

When a liver cells senses it has been infected by hepatitis C virus, the cell activates an inflammatory response that includes the release of chemokines, signaling to immune cells to come to the liver. This proposal seeks to understand how sensing of HCV leads to chemokine production and how the functions of immune and infected liver cells change when they come in contact with one another. In doing so, we will learn how our body's response to HCV causes inflammation of the liver, which may lead to novel treatments.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Colorado Denver
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