Maternal effect on offspring immunity against hepatitis B virus

母体对后代乙型肝炎病毒免疫力的影响

• 批准号: 10208644
• 负责人: OMID AKBARI
• 金额: $ 64.17万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-03 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208644
• 关键词: Affect; Anti-Inflammatory Agents; Butyric Acids; CD8-Positive T-Lymphocytes; Cessation of life; Child; Chronic; Chronic Hepatitis B; Cirrhosis; Development; Exposure to; Female; Gene Expression; Genomic DNA; Goals; Grant; Hepatic; Hepatitis B Therapy; Hepatitis B Transmission; Hepatitis B Virus; Hepatocyte; Horizontal Disease Transmission; Human; Immunity; Immunosuppression; Impairment; Inflammatory; Injections; Kupffer Cells; Lead; Life; Liver; Liver diseases; Molecular; Mothers; Mus; Myeloid-derived suppressor cells; Names; Patients; Phenotype; Population Analysis; Primary carcinoma of the liver cells; Research; Role; Serum; T cell response; T-Lymphocyte; Testing; Transgenic Mice; Vertical Disease Transmission; Viral; Viral Antigens; Virus; Virus Diseases; Virus Replication; acute infection; anti-hepatitis B; chronic infection; dysbiosis; fetal immunity; gut microbiota; macrophage; male; microbial; mouse model; novel therapeutics; offspring; phenotypic biomarker; programmed cell death ligand 1; programmed cell death protein 1; pup; transmission process; viral DNA; viral transmission

Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in 0.5-1 million deaths every year. Most chronic HBV carriers acquired the virus early in life from their infected mothers. In contrast to the mother-to-child transmission (i.e., vertical transmission), patients who acquired HBV from unrelated inviduals (i.e., horizontal transmission) will usually develop self-limited acute infection. Why vertical transmission leads to chronic infection whereas horizontal transmission leads to self- limited acute infection was unclear. Our recent studies indicated that HBV in the mothers could suppress anti- HBV immunity in her children to promote HBV persistence in the latter. HBV has a very narrow host range, which has greatly hampered its research. We have recently developed a mouse model to study the maternal effect on HBV persistence in her offspring. By crossing female hemizygous HBV transgenic mice to male naïve mice, we obtained non-transgenic mouse pups. When these non-transgenic mouse pups were injected with the HBV genomic DNA by hydrodynamic injection, the HBV replication persisted in the mouse liver for up to 28 weeks. This is in contrast to control mice born to non-transgenic mothers, which cleared HBV after 3-4 weeks of HBV DNA injection. Our further studies indicated that maternal HBV could condition hepatic macrophages of the offspring, which would undergo M2 polarization to suppress HBV-specific CD8+ T cells after the introduction of HBV into the mouse liver. The goal of this application is to continue our previous studies to further understand the maternal effect on offspring immunity against HBV. Specifically, we will determine how HBV in the mother impacts HBV-specific CD8+ T cells and hepatic macrophages of the offspring. We will also determine whether and how maternal HBV affects the myeloid-derived suppressor cells (MDSCs) of the offspring and the possible roles of MDSCs in the suppression of anti-HBV immunity in the offspring. Finally, we will investigate the possible effect of gut microbiota and their metabolites, specifically butyric acid, on HBV replication and anti-HBV immunity of the offspring. The proposed studies will provide important information for us to understand the mechanism of HBV persistence after its mother-to-child transmission and facilitate the development of novel therapeutic options for chronic HBV patients.

乙肝病毒可导致严重的肝病，包括肝硬变和肝细胞癌 (肝细胞癌)。世界上大约有2.5亿人长期感染这种病毒， 每年造成50万至100万人死亡。大多数慢性乙肝病毒携带者在生命早期就通过他们的 受感染的母亲。与母婴传播(即垂直传播)相比， 从无关个体(即水平传播)获得的乙肝病毒通常会发展为自限性急性肝炎。 感染。为什么垂直传播导致慢性感染，而水平传播导致自身感染 有限的急性感染尚不清楚。我们最近的研究表明，母亲体内的乙肝病毒可以抑制抗-HBs 在她的孩子中乙肝免疫促进了乙肝病毒在后者的持久化。乙肝病毒的宿主范围非常窄，这 极大地阻碍了它的研究。我们最近开发了一个小鼠模型来研究母体对母体的影响 在她的后代中，乙肝病毒持续存在。通过将雌性半合子乙肝转基因小鼠与雄性天真小鼠杂交，我们 获得了非转基因小鼠幼鼠。当这些非转基因小鼠被注射乙肝病毒时 通过流体动力注射基因组DNA，乙肝病毒在小鼠肝脏中的复制持续了长达28周。 这与非转基因母亲生下的对照组小鼠形成鲜明对比，后者在感染HBV3-4周后清除了HBV病毒 DNA注射。我们的进一步研究表明，母体乙肝病毒对小鼠肝巨噬细胞有调节作用。 子代，在引入后将经历M2极化以抑制HBV特异性CD8+T细胞 乙肝病毒进入小鼠肝脏。本申请的目的是继续我们之前的研究，以进一步了解 母体对后代抗乙肝免疫的影响。具体地说，我们将确定母亲体内的乙肝病毒 影响子代的乙肝病毒特异性CD8+T细胞和肝巨噬细胞。我们还将确定是否 以及母体乙肝病毒如何影响子代的髓系来源的抑制细胞(MDSCs)以及可能的 骨髓间充质干细胞在子代抗乙肝免疫抑制中的作用最后，我们将调查可能的 肠道微生物区系及其代谢产物，特别是丁酸对乙肝病毒复制和抗乙肝免疫的影响 子孙后代的。建议的研究将提供重要的资料，让我们了解 乙肝病毒在母婴传播后的持久性和促进新治疗方案的开发 适用于慢性乙肝患者。