乙型肝炎病毒逃避肝细胞的先天免疫，但是激活巨噬细胞产

StephenW

Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages

    Xiaoming Cheng1, Yuchen Xia1, Elisavet Serti1, Peter Daniel Block1, Michelle Chung1, Kazuaki Chayama2, Barbara Rehermann1 andT. Jake Liang1,*

Version of Record online: 20 NOV 2017

DOI: 10.1002/hep.29348

© 2017 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Issue
Hepatology

Volume 66, Issue 6, pages 1779–1793, December 2017
    1    Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
    2    Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan

Email: T. Jake Liang ([email protected])

*T. Jake Liang, M.D.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Building 10
Room 9B16
10 Center Drive
Bethesda, MD 20814
Tel: +1-301-496-1721
E-mail: [email protected]

    Potential conflict of interest: Nothing to report.

    Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Yuchen Xia is partly sponsored by The International Liver Cancer Association (ILCA)-Fellowship.



Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune-mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779–1793)

StephenW

乙型肝炎病毒逃避肝细胞的先天免疫，但是激活巨噬细胞产生细胞因子

    成晓明1，夏雨辰1，Elisavet Serti1，彼得丹尼尔Block1，米歇尔中1，茶山明2，芭芭拉Rehermann1和T。 Jake Liang1，*

在线记录版本：2017年11月20日

DOI：10.1002 / hep.29348

©2017由美国肝病研究协会。这篇文章是美国政府雇员的贡献，他们的工作在美国是公共领域。

问题
肝病

第66卷，第6期，第1779-1793页，2017年12月
    1国立卫生研究院肝病研究所，糖尿病，消化和肾脏疾病研究所，马里兰州贝塞斯达
    2日本广岛大学消化病与代谢系

电子邮件：T. Jake Liang（[email protected]）

* T。杰克·梁先生
国立卫生研究院肝病研究所，国立糖尿病，消化和肾脏疾病研究所
10号楼
9B16室
10中央车道
Bethesda，MD 20814
电话：+ 1-301-496-1721
电子邮箱：[email protected]

    潜在的利益冲突：无需报告。

    美国国立卫生研究院国立糖尿病与消化和肾脏疾病研究所室内研究计划支持。夏雨辰部分由国际肝癌协会（ILCA）资助。



乙型肝炎病毒（HBV）特异性感染肝细胞并引起免疫介导的肝损伤。乙肝病毒与感染早期的先天免疫相互作用，肝细胞或肝脏中的其他细胞，仍然存在争议。为了解决这个问题，我们利用各种人类细胞培养模型和人源化的Alb-uPA / SCID小鼠。所有这些模型尽管有强有力的HBV复制，但仍不能产生干扰素（IFN）应答。为了阐明干扰素应答缺乏的机制，我们检测了HBV是否能主动抑制肝细胞的先天性免疫功能。通过用已知的IFN信号传导途径的诱导剂处理HBV感染的细胞，我们没有观察到HBV感染或下游IFN响应的改变。我们发现DNA固有的传感通路在肝细胞中活性很差，与HBV先天性免疫识别一致。在暴露于高水平的HBV时，人巨噬细胞可以被激活，具有增加的炎性细胞因子表达。结论：HBV表现为“隐形”病毒，不会感染，也不会积极干扰感染肝细胞的固有免疫。巨噬细胞能够感知HBV，但需要暴露于高HBV滴度，可能解释急性感染期间的长时间“窗口期”和HBV慢性感染的倾向。 （Hepatology 2017; 66：1779-1793）