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

酒精通过损害肝细胞的先天免疫促进乙型肝炎的进展

• 批准号: 10526257
• 负责人: NATALIA ALEKSANDR OSNA
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-28 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526257
• 关键词: APOCEC3G gene; Acceleration; Adipose tissue; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Antigens; Attenuated; Cells; Chronic Hepatitis B; Circulation; Clinical; Clinical Trials; Communication; Complex; Cytotoxic T-Lymphocytes; Death Rate; Development; Environmental Exposure; Ethanol; Event; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feedback; Functional disorder; Future; Genes; Goals; Grant; Heart; Hepatitis B; Hepatocyte; High Fat Diet; IRF3 gene; Immune; Impairment; Incidence; Infection; Inflammation; Interferon Activation; Interferons; Intervention; Liver; Lung; Macrophage; Malignant Neoplasms; Mediating; Modality; Monitor; Mus; Natural Immunity; Nebraska; Organ; Outcome; Pancreas; Pathogenesis; Pathology; Pathway interactions; Patients; Preventive vaccine; Qualifying; RARRES3 gene; Regulation; Research; Research Personnel; Resistance; Resolution; STAT1 gene; Signal Transduction; Spleen; Stimulator of Interferon Genes; Tissues; Transgenic Organisms; Translating; Unsaturated Fatty Acids; Viral; Viral Genes; Viral Load result; Viral Markers; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; alcohol abuser; alcohol effect; alcohol exposure; biomarker development; clinical practice; end stage disease; end stage liver disease; experience; experimental study; extracellular vesicles; gene induction; immune activation; intrahepatic; liver injury; mortality; pre-clinical; protective effect; response; systemic inflammatory response; vaccine access

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.

该项目是暴露组和酒精 P50 拨款的一部分。它的重点是了解与生俱来的 免疫机制，环境中暴露于乙醇代谢物会增加 乙型肝炎病毒 (HBV) 感染并促进其持续存在和肝损伤。尽管有预防性疫苗 据估计，全球慢性乙型肝炎病毒携带者人数高达 2.5 亿，其中 年死亡率80万。慢性乙型肝炎病毒感染的发生率、病毒载量和结果 酗酒的乙型肝炎患者的终末期疾病发生率较高，但这些背后的机制 事件仍不清楚。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）反应。我们还将研究巨噬细胞对 激活干扰素刺激基因 (ISG) 并降低肝细胞中的 HBV 水平。一种抗病毒药物 ISG、APOBEC3G 具有特别重要的意义，因为它可以降解 HBV cccDNA。这种巨噬细胞-肝细胞 通讯是通过细胞外囊泡（EV）介导的。然而，电动汽车分泌的保护作用 当细胞接触酒精时，巨噬细胞产生的酶可能会被破坏。高脂肪饮食进一步加剧肝炎 B 酒精增强发病机制。我们的中心假设是：接触乙醇代谢物会损害 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直接通过限制 抗病毒 ISG 诱导，并间接通过破坏 EV 介导的保护性串扰 巨噬细胞和肝细胞，从而促进肝内病毒传播并增强发病机制。这 乙醇对表达 HBV 的肝细胞先天免疫的抑制作用可能会进一步增强 细胞暴露于不饱和脂肪酸。对于这项研究，我们提出了 3 个目标： 目标 1：研究通过 RIG1-MAVS- 激活 ISG 对肝细胞中 HBV 感染的调节 IRF3 或 cGAS-STING-IRF3 和 JAK-STAT1/2 途径暴露于乙醇代谢物和 不饱和脂肪酸。 目标 2：在酒精和不饱和脂肪酸暴露的情况下，评估 EV 介导的串扰 乙型肝炎病毒感染的肝细胞和巨噬细胞之间的相互作用，通过先天免疫调节抗病毒保护。 目标 3：阐明乙醇和高脂饮食对 HBV 表达、ISG 诱导和肝脏的贡献 转基因 HBV 复制小鼠的脂肪变性/炎症，并研究这些暴露是否影响其他 这些小鼠的器官/组织（肺、心脏、脾脏、胰腺、脂肪组织）。 所获得的信息具有通过以下方式转化为临床实践和干预措施的巨大潜力： 先天免疫功能障碍的生物标志物的开发和可能的治疗方法的确定 目标。