Innate immune recognition of the single stranded RNA (ssRNA) virus and induction of a strong antiviral immunity play a critical role in the outcome of hepatitis C virus (HCV) infection. Alcohol consumption contributes to inflammation, innate immune defects, and HCV-induced progression of liver disease. HCV interacts with immune cells in the liver through interactions between HCV-infected hepatocytes or in the circulation in the form of infectious virus particle or its abundantly produced viral proteins. HCV represents danger signals for the host through Toll like receptor 7 and 8 that recognize ssRNA, TLR3 that senses dsRNA or TLR2 that is activated by HCV core and NSS proteins. These TLRs are expressed in immune cells and in hepatocytes but little is known about the role of interactions between HCV infected hepatocytes and innate immune cells such as monocytes and dendritic cells (DC) in the pathomechanism of HCV infection. Our studies demonstrated that chronic HCV infection as well as alcohol treatment results in increased monocyte pro-inflammatory activation but impaired IFN production by plasmacytoid dendritic cells. Therefore, we hypothesize that HCV and alcohol, individually and together, interfere with antiviral host defense at the level of viral recognition receptors and by subverting pivotal functions of monocytes and dendritic cells. We propose that interaction of innate immune cells (monocytes, macrophages, dendritic cells) with HCV-infected hepatocytes modulates their function and/or phenotype to result in impaired innate and adaptive immunity. We hypothesize that HCV-mediated signals play a role in HCV-induced alterations in dendritic cells (mDCI, mDC2, pDC) and contribute to the reduced T cell responses in HCV infection by induction of CD4+CD25+ regulatory T cells.
The Specific Aims of this proposal are: 1. To determine the effect of alcohol exposure and HCV on the function and phenotype of monocytes and macrophages, 2. To investigate mechanisms by which alcohol modulates myeloid Type I dendritic cell-mediated defects of T cell activation in chronic HCV infection, 3. To evaluate the effects of alcohol on IFN-lambda in HCV infection, 4. To assess the effect of TLR-mediated/HCV-induced signals in altering dendritic cell functions.

Public Health Relevance

Hepatitis C virus (HCV) results in chronic liver inflammation which leads to chronic liver disease. Alcohol consumption worsens HCV liver disease. The common target of both HCV and alcohol use is the immune system where both HCV and alcohol use result in activation of inflammatory cells and inhibition of antigen presentation. Our goal is to identify mechanisms by which HCV and alcohol induce abnormalities in innate immune cells by using specimens from patients with HCV infection and in vitro methods.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AA014372-11S1
Application #
8729121
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wang, Joe
Project Start
2003-09-15
Project End
2018-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$15,001
Indirect Cost
$6,001
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Bukong, Terence N; Kodys, Karen; Szabo, Gyongyi (2014) A Novel Human Radixin Peptide Inhibits Hepatitis C Virus Infection at the Level of Cell Entry. Int J Pept Res Ther 20:269-276
Bukong, Terence N; Momen-Heravi, Fatemeh; Kodys, Karen et al. (2014) Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS Pathog 10:e1004424
Saha, Banishree; Szabo, Gyongyi (2014) Innate immune cell networking in hepatitis C virus infection. J Leukoc Biol 96:757-66
Bukong, Terence N; Hou, Wei; Kodys, Karen et al. (2013) Ethanol facilitates hepatitis C virus replication via up-regulation of GW182 and heat shock protein 90 in human hepatoma cells. Hepatology 57:70-80
Hou, Wei; Bukong, Terence N; Kodys, Karen et al. (2013) Alcohol facilitates HCV RNA replication via up-regulation of miR-122 expression and inhibition of cyclin G1 in human hepatoma cells. Alcohol Clin Exp Res 37:599-608
Zhang, Shuye; Kodys, Karen; Li, Kui et al. (2013) Human type 2 myeloid dendritic cells produce interferon-? and amplify interferon-? in response to hepatitis C virus infection. Gastroenterology 144:414-425.e7
Zhang, Shuye; Saha, Banishree; Kodys, Karen et al. (2013) IFN-ýý production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells. J Hepatol 59:442-9
Bukong, Terence N; Kodys, Karen; Szabo, Gyongyi (2013) Human ezrin-moesin-radixin proteins modulate hepatitis C virus infection. Hepatology 58:1569-79
Szabo, Gyongyi; Wands, Jack R; Eken, Ahmet et al. (2010) Alcohol and hepatitis C virus--interactions in immune dysfunctions and liver damage. Alcohol Clin Exp Res 34:1675-86
Dolganiuc, Angela; Szabo, Gyongyi (2009) In vitro and in vivo models of acute alcohol exposure. World J Gastroenterol 15:1168-77

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