在缺乏免疫肝细胞DNA检测的有利于乙肝病毒感染

StephenW

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection

    Martin K. Thomsen1,2, Ramya Nandakumar1,2, Daniela Stadler3, Antje Malo3, Roser Marin Valls1, Fan Wang1, Line S. Reinert1,2, Frederik Dagnæs-Hansen1, Anne Kruse Hollensen1, Jacob Giehm Mikkelsen1,2, Ulrike Protzer3 andSøren R. Paludan1,2,*

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

Version of Record online: 26 JUL 2016

DOI: 10.1002/hep.28685

© 2016 by the American Association for the Study of Liver Diseases.

Issue
Hepatology

Volume 64, Issue 3, pages 746–759, September 2016
Article has an altmetric score of 4



    Supported by the Danish Medical Research Council (12-124330), Fabrikant Einar Willumsens Mindelegat, Fhv. Dir. Leo Nielsen og Hustru Karen Margrethe Nielsens Legat for Lægevidenskabelig Grundforskning, the Aarhus University Research Foundation, and a DFF-Mobilex postdoctoral fellowship (to M.K.T.) funded through the European Union's 7th Framework program.

Abstract

Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a 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 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING). In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type 1 IFN in response to foreign DNA or HBV infection and mice lacking STING or cyclic guanosine monophosphate-adenosine monophosphate synthase 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 possesses 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. 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. (Hepatology 2016;64:746-759)

StephenW

在缺乏免疫肝细胞DNA检测的有利于乙肝病毒感染

    马丁K. Thomsen1,2，Ramya Nandakumar1,2，丹妮拉Stadler3，安特耶Malo3，罗瑟马林Valls1，范Wang1，线S. Reinert1,2，弗雷德里克Dagnæs-Hansen1，安妮·克鲁斯Hollensen1，雅各Giehm Mikkelsen1,2，乌尔里克Protzer3andSøren R. Paludan1,2，*

    生物医药和，奥胡斯大学，奥尔胡斯，丹麦的1系
    2奥胡斯研究中心先天免疫，奥胡斯大学，奥尔胡斯，丹麦
    病毒学研究所3，慕尼黑工业大学/亥姆霍兹慕尼黑中心，慕尼黑，德国

2016年7月26日：记录在线版本

：10.1002 / hep.28685

2016年©由美国肝病研究学会。

问题
肝病

64卷，第3期，页746-759，2016年9月
文章中4的比分altmetric



    由丹麦医学研究理事会（12-124330），Fabrikant埃纳尔里斯Mindelegat，FHV支持。目录。狮子座尼尔森OG Hustru卡伦·玛格丽特·Nielsens Legat为LægevidenskabeligGrundforskning，奥胡斯大学研究基金会和DFF-MOBILEX博士后研究（以M.K.T.）通过欧盟第七框架计划资助。

抽象

乙型肝炎病毒（HBV）是一种主要的人类病原体，并约有三分之一的世界人口的将暴露于在其一生中的病毒。乙肝病毒感染的肝细胞，在那里它复制其DNA和感染可导致急性和慢性肝炎肝硬化和肝细胞癌的危险性高。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1型干扰素（IFN）生产;与这种情况发生时，通过依赖于DNA的传感器环磷酸鸟苷，腺苷一磷酸合酶和IFN基因的下游衔接蛋白刺激（STING）的路径。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，肝细胞不响应于外源DNA或HBV感染和缺乏STING或环磷酸鸟苷，一磷酸腺苷酶显示出不变的腺病毒 - HBV模型来控制感染的能力的小鼠产生1型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。结论：缺乏肝细胞的功能与生俱来的DNA检测途径妨碍乙肝病毒感染的有效先天控制;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能促进这种细胞类型的能力薄弱，清除HBV感染。 （2016年肝病; 64：746-​​759）