This proposal is designed to investigate the following hypothesis: The consumption of alcohol by mice is associated with suppression of the early innate response mediated by the innate immune system, which compromises the ability of the host to control a hepatotropic virus infection. The uncontrolled viral replication elicits an inflammatory response that produces profound pathologic effects in the liver. An established approach to studying mechanisms of liver disease is the use of mouse models. The innate, host- defense mechanisms of mice are considerable homologous to that of human beings. We have developed an animal model in which we utilize a hepatotropic viral infection of mice, murine cytomegalovirus (MCMV), and an ethanol-feeding regime (Lieber-Decarli diet), to study the resultant effects on innate immunity in C57BL/6 mice. It has been previously shown that an early immune response that is mediated by the innate immune system is critical for control of MCMV infection. The specific immune factors of this required response have been well characterized and have been shown to be primarily mediated by macrophages, NK cells, and associated cytokines (i.e. IL-12 and IFN-gamma). Preliminary data indicates that alcohol-fed mice are substantially more susceptible to virus infection, suggesting a possible suppression of the innate immune response following alcohol consumption. The proposed investigated will examine the activation and production of critical aspects of the innate response in order to identify any deleterious or suppressive effects of the innate response following consumption of alcohol. The findings of this study will be relevant to future study of the antiviral effect or mechanisms of the innate immune response as well as aide in the delineation of mechanisms by which alcohol can increased susceptibility to infectious agents.
