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Hepatitis B virus e antigen in viral persistence

乙型肝炎病毒e抗原在病毒持续存在中

基本信息

批准号：
10159091
负责人：
J.-H. James Ou
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-20 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159091
关键词：
Adult Affect Antigen Receptors CD8-Positive T-Lymphocytes Cells Cessation of life Chronic Chronic Hepatitis Chronic Hepatitis B Cirrhosis Clinical Core Protein Development Female Genes Genomic DNA Goals Grant Hepatitis B Therapy Hepatitis B Virus Hepatitis B e Antigens Hepatocyte Horizontal Disease Transmission Human Human Herpesvirus 4 Immune Tolerance Immune response Impairment Injections Knowledge Kupffer Cells Lead Length Life Liver Liver diseases Mediating Mothers Mus Mutation Names Nucleotides Pathogenesis Patients Primary carcinoma of the liver cells Research Risk Symptoms T cell response Testing Transgenic Mice Vertical Disease Transmission Viral Viral Genome Virus Virus Diseases Virus Replication acute infection chronic infection human pathogen improved in utero in vivo male maternal condition mouse model mutant offspring promoter pup receptor viral DNA

项目摘要

Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). There are approximately 350 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 through vertical transmission. In contrast, patients who acquired HBV from other adults through 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 is unclear. 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 the 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 seven months. 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 the maternal HBV e antigen (HBeAg) could condition the Kupffer cells of the offspring, which would undergo M2 polarization to support HBV persistence upon re-stimulation by HBeAg. The goal of this application is to continue these previous studies to further investigate how HBeAg interacts with Kupffer cells. Specifically, we will determine how HBeAg stimulates Kupffer cells and to identify the putative HBeAg receptor in these cells. We will also determine whether HBeAg by itself is sufficient to condition Kupffer cells of the offspring to support HBV persistence and whether Kupffer cells by themselves are sufficient to support HBV persistence. We will also test the hypothesis that HBeAg conditions Kupffer cells in utero to suppress the immune response to HBV in the offspring. Finally, we will study the HBV basal core promoter mutant, which has reduced expression of HBeAg and is associated with chronic hepatitis and an increased risk for HCC, to test whether this reduction of HBeAg expression leads to the partial loss of immune tolerance. The proposed studies will provide important information for us to understand the mechanism of HBV persistence after vertical transmission and to improve the treatments for chronic HBV patients.

B型肝炎病毒（HBV）可导致严重的肝脏疾病，包括肝硬化和肝细胞癌（HCC）。世界上大约有3.5亿人长期感染这种病毒，每年造成50 - 100万人死亡。大多数慢性HBV携带者在生命早期从他们的父母那里获得病毒。通过垂直传播感染的母亲。相比之下，通过以下途径从其他成人获得HBV的患者，水平传播通常会发展为自限性急性感染。为什么垂直传播会导致慢性感染，而水平传播导致自限性急性感染尚不清楚。HBV有一个非常寄主范围窄，这极大地限制了其研究。我们最近开发了一种小鼠模型，研究母亲对HBV在后代中持续存在的影响。通过杂交雌性半合子HBV转基因通过将小鼠转化为雄性幼稚小鼠，我们获得了非转基因小鼠幼崽。当这些非转基因小鼠幼崽通过流体动力学注射将HBV基因组DNA注射到小鼠体内，HBV复制持续存在肝脏长达7个月。这与非转基因母亲所生的对照小鼠相反， HBV DNA注射后3-4周。我们进一步的研究表明，母亲HBV e抗原 HBeAg可调节子代Kupffer细胞，使其发生M2极化以支持HBV HBeAg再刺激后持续存在。本申请的目的是继续这些先前的研究，进一步研究HBeAg如何与枯否细胞相互作用。具体来说，我们将确定HBeAg如何刺激 Kupffer细胞，并确定这些细胞中的假定HBeAg受体。我们还将确定HBeAg是否本身足以调节后代的枯否细胞以支持HBV持续存在，细胞本身就足以支持HBV的持续存在。我们还将检验HBeAg 条件库普弗细胞在子宫内，以抑制免疫反应的乙肝病毒在后代。最后，我们将研究 HBV基本核心启动子突变体，其具有降低的HBeAg表达，并且与慢性乙型肝炎相关。乙型肝炎和肝癌风险增加，以测试HBeAg表达的减少是否导致部分免疫耐受的丧失。建议的研究将为我们了解 HBV垂直传播后持续存在的机制和改善慢性HBV治疗的研究患者