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 HCV infection. Alcohol consumption contributes to inflammation, innate immune defects, and HCV-induced progression of liver disease. Toll like receptor 7 and 8 recognizing ssRNA expressed in innate immune cells such as monocytes and dendritic cells (DC), have recently been novel targets in HCV therapy;however, little is known about the role of TLR7/8 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 interferes with antiviral host defense at the level of viral recognition receptors and by subverting pivotal functions of monocytes and dendritic cells. We propose that by modulating TLR7/8 activation in innate immune cells, HCV activates inflammatory pathways and alters IFN induction. We further postulate that alcohol exposure of innate immune cells alters TLR7/8-induced signaling. We hypothesize that TLR7/8-mediated signals play a role in HCV-induced alterations in myeloid dendritic cells and contribute to the reduced T cell responses in HCV infection by induction of CD4+CD25+ regulatory T cells. We further propose that alcohol amplifies defects in innate immune responses of HCV infected patients by interfering not only with TLR7/8 signaling but also with dendritic cell-induced T cell activation.
The Specific Aims of this proposal are: 1. To determine the effect of alcohol exposure on TLR8-mediated signals in inflammatory activation in monocytes and macrophages in HCV infection by investigating the expression of TLR8 and the effect of TLR8 activation on MyD88-dependent signaling and Type I IFN-induction pathways and the effects of uptake of HCV-infected hepatoma cells in monocytes from HCV infected patients. 2. To investigate mechanisms by which alcohol modulates myeloid dendritic cell-mediated defects of T cell activation in chronic HCV infection by evaluating the effect of TLR8 activation and uptake of HCV-infected hepatoma cells on monocyte-derived DCs (mDC).differentiation, maturation, and T cell activating capacity. 3. To evaluate the effect of alcohol on IFN-lambda in HCV infection by testing dendritic-cell-mediated induction of regulatory T cells. 4. To assess the effect of alcohol on the role of TLR7 in plasmacytoid dendritic cells of HCV infected patients. Results from these experiments will provide novel information about the effects of alcohol on antiviral immunity and its role in the pathomechanisms of chronic HCV infection.

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- specific immune cell functions. The goal of this application is to identify specific mechanisms by which HCV and alcohol induce these abnormalities in innate immune cells by using specimens from patients with chronic HCV infection and in vitro methods to study the effects of alcohol.

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 #
5R37AA014372-10
Application #
8318308
Study Section
Special Emphasis Panel (ZRG1-DIG-C (03))
Program Officer
Wang, Joe
Project Start
2003-09-15
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$355,764
Indirect Cost
$139,494
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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