乙型肝炎病毒DNA是cGAS / STING途径的底物，但在感染的肝细胞

StephenW

Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes
by Lise Lauterbach-Rivière 1,*,†, Maïwenn Bergez 1 [OrcID] , Saskia Mönch 1, Bingqian Qu 2 [OrcID] , Maximilian Riess 1 [OrcID] , Florian W. R. Vondran 3,4, Juliane Liese 5 [OrcID] , Veit Hornung 6, Stephan Urban 2,7 and Renate König 1,8,9,* [OrcID]
1
Host–Pathogen Interactions, Paul-Ehrlich-Institut, 63225 Langen, Germany
2
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
3
Regenerative Medicine and Experimental Surgery (ReMediES), Department of General, Visceral and Transplant Surgery, Hannover Medical School, 30625 Hannover, Germany
4
German Centre for Infection Research (DZIF), Hannover-Braunschweig, 38124 Braunschweig, Germany
5
Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, 35392 Giessen, Germany
6
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
7
German Center for Infection Research (DZIF), 69120 Heidelberg, Germany
8
German Center for Infection Research (DZIF), 63225 Langen, Germany
9
Sanford Burnham Prebys Medical Discovery Institute, Immunity and Pathogenesis Program, La Jolla, CA 92037, USA
*
Authors to whom correspondence should be addressed.
†
Current Address: Institute of Virology, Saarland University Medical Center, 66421 Homburg/Saar, Germany.
Viruses 2020, 12(6), 592; https://doi.org/10.3390/v12060592
Received: 27 April 2020 / Revised: 24 May 2020 / Accepted: 28 May 2020 / Published: 29 May 2020
(This article belongs to the Special Issue Innate Immune Sensing of Viruses and Viral Evasion)
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Abstract
Hepatitis B virus (HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway. View Full-Text
Keywords: hepatitis B virus (HBV); innate immunity; STING; cGAS; innate immune sensing; interferon response

StephenW

乙型肝炎病毒DNA是cGAS / STING途径的底物，但在感染的肝细胞中未检测到
作者：LiseLauterbach-Rivière1，*，†，MaïwennBergez 1 [OrcID]，SaskiaMönch1，Bingqian Qu 2 [OrcID]，Maximilian Riess 1 [OrcID]，Florian WR Vondran 3,4，Juliane Liese 5 [OrcID]， Veit Hornung 6，Stephan Urban 2,7和RenateKönig1,8,9，* [OrcID]
1个
病原菌相互作用，Paul-Ehrlich-Institut，63225 Langen，德国
2
海德堡大学医院分子病毒学传染病学系，德国海德堡69120
3
汉诺威医学院普通内脏和移植外科系再生医学与实验外科（ReMediES），德国汉诺威30625
4
德国感染研究中心（DZIF），汉诺威-不伦瑞克，38124不伦瑞克，德国
5
吉森Justus-Liebig大学吉萨大学普外科和胸外科
6
德国慕尼黑路德维希-马克西米利安斯大学基因中心和生物化学系，德国慕尼黑81377
7
德国感染研究中心（DZIF），德国海德堡69120
8
德国感染研究中心（DZIF），德国63225
9
Sanford Burnham Prebys医学发现研究所，免疫和发病机制计划，拉荷亚，CA 92037，美国
*
应与之联系的作者。
†
当前地址：德国萨尔州萨尔兰德大学医学中心病毒学研究所，邮编66421。
病毒2020，12（6），592; https://doi.org/10.3390/v12060592
收到：2020年4月27日/修订：2020年5月24日/接受：2020年5月28日/发布：2020年5月29日
（本文属于《病毒与病毒逃逸的特刊先天免疫》）
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乙型肝炎病毒（HBV）慢性感染是肝细胞癌的重要危险因素。对HBV感染的先天免疫反应尚有争议。特别是，病毒逃逸机制了解甚少。我们的研究表明，HBV RNA在具有免疫能力的骨髓细胞中不具有免疫刺激性。相反，来自病毒颗粒和DNA复制中间体的HBV DNA具有免疫刺激性，并被环状GMP-AMP合酶（cGAS）和干扰素基因刺激剂（STING）感测。我们显示，与骨髓细胞相比，原代人肝细胞表达的DNA传感器水平降低。然而，当以足够的量转染时，肝细胞可以对HBV松弛圆形DNA（rcDNA）作出反应，但对HBV感染则无反应。最后，我们的数据表明HBV感染不会主动抑制DNA感应途径。总之，在被感染的肝细胞中，HBV通过（i）产生非免疫刺激性RNA，（ii）避免通过cGAS / STING对其DNA的感测而没有主动抑制该途径，从而被动地逃避了细胞传感器对核酸的识别。查看全文
关键字：乙型肝炎病毒（HBV）；先天免疫;刺; cGAS；先天免疫感应干扰素反应

StephenW

https://www.mdpi.com/1999-4915/12/6/592/htm