Studies have shown that alcohol consumption is associated with a suppression of immune responses to infectious agents. The suppression of immune responses, especially cell-mediated immune responses, results in an increased susceptibility to infectious agents including hepatotropic bacteria and viruses. Studies done in my laboratory have shown that alcohol consumption by mice either with the Lieber DeCarli or with a more chronic ETOH in water protocol results in an inability to control the infection by murine cytomegalovirus (MCMV) that results in a prolonged liver infection and hepatitis. Alcohol consumption was also associated with alterations in innate responses to the virus (e.g., decreased IL-12 and IFN-gamma production). The hypothesis that will be addressed in this application is that chronic alcohol consumption by mice affects the induction of the innate and acquired immune responses to hepatotropic viruses early in the infection and in the liver that ultimately results in a greater and more prolonged hepatic infection in the mice that consume alcohol. This increase in viral numbers in the liver results in a prolonged (chronic) accumulation of NK cells and CD8+ T cells in the liver, which mediate prolonged liver damage. It is also hypothesized that the described nonspecific activation of CD8+ T cells associated with chronic alcohol consumption by mice results in accumulation of activated CD8+ T cells in the liver that mediate hepatocyte killing. Mechanistic studies to address these hypotheses will be done by addressing the following specific aims: 1.To define the effects of alcohol consumption with an ethanol in drinking water protocol on the production of viral antigen-specific CD8+ T cells and traffic of antigen-specific CD8+ T cells to the liver. 2. To define the effects of chronic consumption of alcohol on the induction of cellular and humoral immune responses to MCMV induced by vaccination with DNA vaccines that incorporate major and minor class I MHC-restricted epitopes to induce CD8+ T cells and an intact virus vaccine to induce antibody responses. 3. To define the effects of alcohol consumption on the innate responses to MCMV that would affect the production of antigen-specific CD8+T cells. 4. To define the role of NK cells in the hepatitis associated with MCMV infection of alcohol-fed mice.
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