Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an overall prevalence of ~2%, and an estimated 200 million chronically infected people worldwide. A substantial body of evidence, including work from our laboratory, supports the concept that early events in the coordination and nature of multi-cellular immune responses are critical in determining whether the virus is cleared or whether persistence is established. However, very little is known about the role of non-parenchymal liver cells (NPCs) in mediating anti-HCV responses. We propose to study how plasmacytoid dendritic cells, Kupffer cells and liver sinusoidal endothelial cells sense HCV infection. We present evidence that NPCs can respond to a viral product of hepatitis C (known as a pathogen-associated molecular pattern or PAMP) by producing high levels of Type III IFNs (interferon lambda 3). These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. Moreover, we have demonstrated that NPCs express HCV core after inoculation with virus or co-culture with infected hepatocytes. We will determine how NPC-derived proteins can inhibit viral replication. Furthermore, we will explore the specific mechanisms by which HCV core protein induces regulatory CD4+ T cells, thus linking innate and adaptive immune responses. The personnel involved in this application include graduate student, post-doctoral fellow and faculty.

Public Health Relevance

The importance of chronic hepatitis C viral infection, that afflicts several million Americans, cannot be overstated. In a large proportion of patients, HCV progression leads to cirrhosis and end-stage liver disease. This application will examine how specific cells that comprise the liver recognize HCV infection in order to identify potential novel targets for therapy.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103361-02
Application #
8662190
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Giugliano, Silvia; Kriss, Michael; Golden-Mason, Lucy et al. (2015) Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology 148:392-402.e13
Rosen, Hugo R (2013) Emerging concepts in immunity to hepatitis C virus infection. J Clin Invest 123:4121-30