Alcohol use accelerates the progression of liver disease in chronic hepatitis C (HCV) infection; however, the interactions between alcohol and HCV have not yet been explored. Chronic HCV infection is associated with reduced HCV-specific immune responses, and alcohol use suppresses antigen-specific T cell activation via inhibition of monocyte and dendritic cell (DC) antigen presentation. Both chronic alcohol consumption and chronic HCV infection are independently associated with activation of inflammatory pathways that mediate hepatocellular injury. Thus, we hypothesize that alcohol, HCV interacts to activate non-specific pro-inflammatory cascades in chronic HCV infection, and this process may contribute to progression of liver damage. Based on our preliminary results, we propose that the pattern recognition receptor, toll-like receptor 2 (TLR2), mediates cellular activation by HCV core and NS3 proteins. We further postulate that alcohol may increase inflammatory cell activation by interacting with TLR2-mediated pathways. Our preliminary results show that myeloid DC (dendritic cells), the most potent antigen presenting cell type, have reduced T-cell activation capacity in patients with chronic HCV infection and this can be further decreased by alcohol treatment of DCs. Thus, we propose that alcohol contributes to the persistence of chronic infection in HCV by inhibiting functional maturation of dendritic cells, thereby decreasing antigen-specific T cell activation and viral recognition.
The Specific Aims of this proposal are: 1. To investigate interactions between HCV- and alcohol-induced inflammatory pathways at the protein and mRNA levels and on activation of the nuclear regulatory kB/Rel pathway in normal monocytes and in patients with chronic HCV infection with and without alcohol use or chronic in vitro alcohol treatment. 2. To investigate the pattern recognition receptor, TLR2, as a putative receptor in cell activation by HCV proteins. This will be accomplished by testing cellular activation by HCV proteins in TLR2-transfected CHO and HEK cells and in macrophages of TLR2-deficient mice. The cooperation of TLR2 with other components of the TLR2 receptor complex required for successful transmission of HCV core and NS3 mediated cell activation will be identified by selectively investigating the roles of CD14, TLR 1, and TLR6. 3. To evaluate the interactions between alcohol and HCV proteins on TLR2-mediated cell activation pathways by determining the effects of acute and chronic alcohol treatment on TLR2 expression, gene activation, and TLR2-mediated monocyte activation from normal controls and chronic HCV infected patients. Investigation of downstream elements involved in TLR2-mediated intracellular signaling after stimulation with core and NS3 proteins and their modulation by alcohol will be tested. 4. To delineate the role of TLR2-mediated signaling by HCV core and NS3 proteins in the reduced dendritic cell differentiation in HCV infected patients and to evaluate the effect of alcohol on TLR2-mediated signals in DC development. Results from these studies should reveal molecular and cellular mechanisms by which alcohol interacts with HCV infection to accelerate disease persistence and progression. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014372-04
Application #
7114949
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Gentry, Thomas
Project Start
2003-09-15
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$388,159
Indirect Cost
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
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Punzalan, C S; Bukong, T N; Szabo, G (2015) Alcoholic hepatitis and HCV interactions in the modulation of liver disease. J Viral Hepat 22:769-76
Saha, Banishree; Bruneau, Johanna C; Kodys, Karen et al. (2015) Alcohol-induced miR-27a regulates differentiation and M2 macrophage polarization of normal human monocytes. J Immunol 194:3079-87
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
Zhang, Shuye; Kodys, Karen; Babcock, Gregory J et al. (2013) CD81/CD9 tetraspanins aid plasmacytoid dendritic cells in recognition of hepatitis C virus-infected cells and induction of interferon-alpha. Hepatology 58:940-9
Zhang, Shuye; Saha, Banishree; Kodys, Karen et al. (2013) IFN-? production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells. J Hepatol 59:442-9
Chang, Serena; Kodys, Karen; Szabo, Gyongyi (2010) Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells. Hepatology 51:35-42
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
Szabo, Gyongyi; Dolganiuc, Angela (2008) Hepatitis C and innate immunity: recent advances. Clin Liver Dis 12:675-92, x

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