Hepatitis B virus e antigen in viral persistence

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)。世界上约有3.5亿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 通过垂直传播感染的母亲。相比之下，从其他成年人那里感染乙肝病毒的患者 水平传播通常会发展为自限性的急性感染。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，目前尚不清楚。乙肝病毒有一种很强的 寄主范围狭窄，这极大地阻碍了其研究。我们最近开发了一种老鼠模型来 研究母体对子代体内乙肝病毒持续存在的影响。通过与雌性半合子乙肝病毒转基因杂交 小鼠为雄性幼稚小鼠，我们获得了非转基因小鼠幼崽。当这些非转基因小鼠幼崽 以流体动力注射的方式注射乙肝病毒基因组DNA，在小鼠体内持续复制 肝脏保存时间长达七个月。这与非转基因母亲所生的对照组小鼠形成了鲜明对比，后者被清除了 HBVDNA注射后3~4周。我们的进一步研究表明，母体HBVe抗原 (HBeAg)可以调节后代的Kupffer细胞，这些细胞将经历M2极化来支持乙肝病毒 在HBeAg的再次刺激下的持久性。本应用程序的目标是继续这些先前的研究 进一步研究HBeAg如何与Kupffer细胞相互作用。具体地说，我们将确定HBeAg如何刺激 Kupffer细胞，并鉴定这些细胞中可能的HBeAg受体。我们还将确定HBeAg是否 其本身足以使后代的Kupffer细胞支持乙肝病毒的持久性，以及Kupffer是否 细胞本身就足以支持乙肝病毒的持久性。我们还将测试HBeAg的假设 条件库普弗细胞在子宫中抑制子代对乙肝病毒的免疫反应。最后，我们将研究 乙肝病毒基本核心启动子突变，HBeAg表达减少，与慢性 肝炎和肝细胞癌风险增加，以测试这种HBeAg表达的减少是否导致部分 丧失免疫耐受性。建议的研究将为我们提供重要的资料，让我们了解 垂直传播后乙肝病毒持续存在的机制及改进慢性乙肝的治疗 病人。

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.