缺乏肝细胞免疫的DNA检测的方便乙型肝炎病毒感染

StephenW

Hepatology. 2016 Jun 16. doi: 10.1002/hep.28685. [Epub ahead of print]
Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.Thomsen MK1,2, Nandakumar R1,2, Stadler D3, Malo A3, Valls RM1, Wang F1, Reinert LS1,2, Dagnaes-Hansen F1, Hollensen AK1, Mikkelsen JG1,2, Protzer U3, Paludan SR1,2.
Author information

• 1Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
• 2Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
• 3Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Germany.
  

AbstractHepatitis B virus (HBV) is a major human pathogen and about one third of the global population will be exposed to the virus in their life time. HBV infects hepatocytes where it replicates its DNA and infection can lead to acute and chronic hepatitis with high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type I IFN production, and this occurs through a pathway dependent on the DNA sensor cGAS and the downstream adaptor protein STING. In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type I IFN in response to foreign DNA or HBV infection and mice lacking STING or cGAS exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possess anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. In conclusion, the lack of a functional innate DNA sensing pathway in hepatocytes hampers efficient innate control of HBV infection. This may explain why HBV has adapted to specifically replicate in hepatocytes, and could contribute to the weak capacity of this cell type to clear HBV infection. This article is protected by copyright. All rights reserved.
© 2016 by the American Association for the Study of Liver Diseases.

StephenW

肝病。 2016年16月：10.1002 / hep.28685。 [打印EPUB提前]
缺乏肝细胞免疫的DNA检测的方便乙型肝炎病毒感染。
汤姆森MK1,2，Nandakumar R1,2，施泰德D3，马洛A3，瓦尔斯令吉，王F1，赖纳特LS1,2，Dagnaes汉森F1，Hollensen AK1，米克尔森JG1,2，Protzer U3，Paludan SR1,2。
作者信息

    生物医药，奥胡斯大学，奥尔胡斯，丹麦教研室。
    2Aarhus研究中心先天免疫，奥胡斯大学，奥尔胡斯，丹麦。
    病毒学3Institute，慕尼黑/亥姆霍兹慕尼黑中心，德国技术大学。

抽象

乙型肝炎病毒（HBV）是一种主要的人类病原体，大约三分之一的全球人口将在其生命的时间暴露于病毒。 HBV感染的肝细胞那里复制其DNA和感染可导致急性和慢性肝炎肝硬化和肝癌的高危人群。尽管如此，有乙肝病毒如何建立慢性感染的了解有限。近年来，人们发现，外源DNA强效刺激先天免疫反应，特别是I型干扰素的产生，并且这发生通过依赖于DNA的传感器CGAS和下游接头蛋白STING一个通路。在这项工作中，我们描述了人类和小鼠肝细胞不表达刺痛。因此，肝细胞不产生I型在应对国外DNA或HBV感染，缺乏STING或注册会计师展览不变的腺病毒HBV模型来控制感染的能力小鼠IFN。干扰素的生产中由合成的RNA的施用鼠肝脏的刺激减少病毒感染，从而表明干扰素具有在肝脏抗HBV活性。重要的是，引入在肝细胞特异性STING表达的重新构成的DNA的检测通路，这导致在体内的HBV的改进的控制。总之，由于缺乏在肝细胞中的功能性先天的DNA传感途径的阻碍HBV感染的有效的固有的控制。这也许可以解释为什么乙肝病毒已经适应了在肝细胞中复制明确，并可能有助于此单元格类型，清除乙肝病毒感染的能力弱。本文由版权保护。版权所有。

2016年©由美国肝病研究学会。