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

该项目是P50赠款的一部分，用于麻烦和酒精。它的重点是了解先天的 免疫机制，通过这种机制，环境暴露于乙醇代谢物会增加 B型肝炎病毒（HBV）感染并促进其持续和肝损伤。尽管有预防性疫苗 根据可用性，全世界慢性HBV携带者的数量估计高达2.5亿， 年死亡率为80万。慢性HBV感染的发生率、病毒载量和治疗结果 在酗酒的B型肝炎患者中，终末期疾病的发生率更高，但这些背后的机制 事件仍不明朗。在这里，我们将研究暴露于病毒，酒精和不饱和脂肪酸如何影响 肝细胞中的干扰素（IFN）应答。我们还将研究巨噬细胞对 干扰素刺激基因（ISG）的激活和肝细胞中HBV水平的降低。一种抗病毒药物 ISG（APOBEC 3G）具有特殊的重要性，因为它降解HBV cccDNA。这个巨噬细胞-肝细胞 通信是通过细胞外囊泡（EV）介导的。然而，电动汽车分泌的保护作用 细胞暴露在酒精中时会被破坏。高脂饮食进一步加重肝炎 酒精可增强B发病机制。我们的中心假设是：暴露于乙醇代谢物损害 HBV感染的肝细胞和病毒激活的巨噬细胞中的干扰素信号传导， 抗病毒ISG诱导，并间接地，通过破坏保护性EV介导的串扰之间 巨噬细胞和肝细胞，从而促进肝内病毒传播和增强的发病机制。的 乙醇对表达HBV的肝细胞中先天免疫的抑制作用可通过以下方式进一步增强： 细胞暴露于不饱和脂肪酸。对于这项研究，我们提出了三个目标： 目的1：研究ISGs通过RIG 1-MAVS-1激活对HBV感染肝细胞的调控作用。 IRF 3或cGAS-STING-IRF 3和JAK-STAT 1/2途径， 不饱和脂肪酸 目的2：在酒精和不饱和脂肪酸暴露的环境中，评估EV介导的串扰 在HBV感染的肝细胞和巨噬细胞之间，通过先天免疫调节抗病毒保护。 目的3：阐明乙醇和高脂饮食对HBV表达，ISG诱导和肝脏的影响。 在转基因HBV复制小鼠中的脂肪变性/炎症，并研究这些暴露是否影响其他 器官/组织（肺、心脏、脾、胰腺、脂肪组织）。 所获得的信息具有很强的潜力，可以通过以下方式转化为临床实践和干预措施： 开发先天免疫功能障碍的生物标志物和确定可能的治疗方法 目标的

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.