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: 9795894
• 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/9795894
• 关键词: Affect; Anti-inflammatory; 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; PDCD1LG1 gene; Patients; Phenotype; Population Analysis; Primary carcinoma of the liver cells; Research; Role; SLEB2 gene; 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; gut microbiota; macrophage; male; microbial; mouse model; novel therapeutics; offspring; phenotypic biomarker; 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.

乙型肝炎病毒（HBV）可引起严重的肝脏疾病，包括肝硬化和肝细胞癌 （肝癌）。全球约有2.5亿人长期感染该病毒， 每年导致 5-10 万人死亡。大多数慢性乙型肝炎病毒携带者在生命早期就从其父母那里感染了病毒。 被感染的母亲。与母婴传播（即垂直传播）相反，患者 从无关个体获得乙型肝炎病毒（即水平传播）通常会发展为自限性急性乙型肝炎 感染。为什么垂直传播会导致慢性感染，而水平传播会导致自我感染 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 HBV 可以抑制抗 她的孩子的乙肝免疫力促进了后者乙肝病毒的持续存在。乙型肝炎病毒的宿主范围很窄， 极大地阻碍了其研究。我们最近开发了一种小鼠模型来研究母体对 乙肝病毒在她的后代中持续存在。通过将雌性半合子 HBV 转基因小鼠与雄性幼鼠杂交，我们 获得非转基因小鼠幼崽。当这些非转基因小鼠幼崽注射乙肝病毒时 通过水动力注射基因组DNA，HBV复制在小鼠肝脏中持续长达28周。 这与非转基因母亲所生的对照小鼠形成鲜明对比，后者在 HBV 感染 3-4 周后清除了 HBV DNA注射。我们的进一步研究表明，母体 HBV 可以调节肝巨噬细胞 后代，在引入 乙肝病毒进入小鼠肝脏。该应用程序的目标是继续我们之前的研究以进一步了解 母体对后代乙肝病毒免疫力的影响。具体来说，我们将确定母亲体内的乙型肝炎病毒如何 影响后代的 HBV 特异性 CD8+ T 细胞和肝巨噬细胞。我们还将确定是否 母体 HBV 如何影响后代的骨髓源性抑制细胞 (MDSC)，以及可能的情况 MDSCs 在抑制子代抗 HBV 免疫中的作用。最后，我们将调查可能的情况 肠道微生物群及其代谢物（特别是丁酸）对 HBV 复制和抗 HBV 免疫的影响 的后代。拟议的研究将为我们了解其机制提供重要信息 乙型肝炎病毒在母婴传播后持续存在并促进新治疗方案的开发 对于慢性乙肝患者。