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: 10438648
• 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/10438648
• 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; Persons; 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.

肝炎病毒（HBV）会引起严重的肝病，包括肝硬化和肝细胞癌 （HCC）。世界上约有2.5亿人长期感染该病毒， 每年导致5.1万人死亡。大多数慢性HBV载体从他们的早期就获得了病毒 感染的母亲。与母子传播（即垂直传播）相反，患者 从不相关的不相关（即水平传输）获得的HBV通常会产生自限性急性 感染。为什么垂直传播会导致慢性感染，而水平传播导致自我 有限的急性感染尚不清楚。我们最近的研究表明，母亲的HBV可以抑制抗 她的孩子的HBV免疫力促进后者的HBV持久性。 HBV的主机范围非常狭窄， 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孕产妇对 HBV在她的后代中的持久性。通过将雌性半合子HBV转基因小鼠跨到雄性小鼠，我们 获得了非转基因小鼠幼崽。当这些非转基因小鼠幼崽注入HBV时 基因组DNA通过流体动力注射，HBV复制在小鼠肝脏中持续长达28周。 这与非转基因母亲出生的对照小鼠相反，该母亲在HBV 3-4周后清除了HBV DNA注射。我们的进一步研究表明，材料HBV可以调节 后代，将经历M2极化以抑制引入HBV特异性CD8+ T细胞 HBV进入小鼠肝脏。该应用程序的目的是继续我们以前的研究以进一步了解 孕产妇对抗HBV的后代免疫的影响。具体来说，我们将确定母亲的HBV如何 影响HBV特异性的CD8+ T细胞和后代的肝巨噬细胞。我们还将确定是否 以及母体HBV如何影响后代的髓样衍生的抑制细胞（MDSC）和可能 MDSC在抑制后代抗HBV免疫中的作用。最后，我们将调查可能 肠道菌群及其代谢产物（特别是丁酸）对HBV复制和抗HBV免疫异性的影响 后代。拟议的研究将为我们提供重要的信息，以了解 HBV在其母子传播后的持久性并促进了新型治疗选择的发展 适用于慢性HBV患者。