Alcohol Promotes Hepatitis B Progression by Impairment of Innate Immunity in Liver Cells

这个项目是50英镑暴露物和酒精补助金的一部分。它专注于理解内在

This project is a part of a P50 grant on exposome and alcohol. It is focused on understanding the innate immunity mechanisms, by which environmental exposure to ethanol metabolites increases the levels of hepatitis B viral (HBV) infection and promotes its persistence and liver injury. Despite a prophylactic vaccine availability, the number of chronic HBV carriers is estimated to be as high as 250 million worldwide, with an annual death rate of 800,000. The incidences of chronic HBV -infection, the viral load and the outcomes of end-stage diseases are higher in hepatitis B patients abusing alcohol, but the mechanisms behind these events are still unclear. Here, we will study how exposures to virus, alcohol and unsaturated fatty acids affect interferon (IFN) response in hepatocytes. We will also study the protective effect of macrophages on the activation of interferon-stimulated genes (ISGs) and the reduction of HBV levels in hepatocytes. One anti-viral ISGs, APOBEC3G, is of special importance since it degrades HBV cccDNA. This macrophage-hepatocyte communication is mediated via extracellular vesicles (EVs). However, the protective effects of EVs secreted from macrophages may be ruined when cells are exposed to alcohol. High-fat diet further exacerbates hepatitis B pathogenesis enhanced by alcohol. Our central hypothesis is: that exposure to ethanol metabolites impairs interferon signaling in HBV-infected hepatocytes and virus-activated macrophages both directly, via limiting anti-viral ISG induction, and indirectly, via disrupting the protective EV-mediated crosstalk between macrophages and hepatocytes, thereby promoting intrahepatic viral spread and enhanced pathogenesis. The suppressive effects of ethanol on innate immunity in HBV-expressing hepatocytes may be further enhanced by cell exposure to unsaturated fatty acids. For this study, we proposed 3 Aims: Aim 1: To study the regulation of HBV-infection in hepatocytes by the activation of ISGs via the RIG1-MAVS- IRF3 or the cGAS-STING-IRF3 and the JAK-STAT1/2 pathways under exposure to ethanol metabolites and unsaturated fatty acids. Aim 2: In the settings of alcohol and unsaturated fatty acid exposures, to assess the EV-mediated crosstalk between HBV-infected hepatocytes and macrophages, which regulates anti-viral protection by innate immunity. Aim 3: To elucidate the contribution of ethanol and high-fat diet to HBV expression, ISG induction, and liver steatosis/inflammation in transgenic HBV-replicating mice, and to study whether these exposures affect other organs/tissues (lung, heart, spleen, pancreas, adipose tissue) in these mice. The obtained information has the strong potential to be translated to clinical practice and interventions through the development of biomarkers for innate immunity dysfunction and the identification of possible treatment targets.