Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes.
Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes.
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DOI：
10.1002/hep.30054
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Baumert TF
中科院分区：
文献类型：
--
作者：
Verrier ER;Yim SA;Heydmann L;El Saghire H;Bach C;Turon-Lagot V;Mailly L;Durand SC;Lucifora J;Durantel D;Pessaux P;Manel N;Hirsch I;Zeisel MB;Pochet N;Schuster C;Baumert TF
慢性乙型肝炎病毒（HBV）感染是世界范围内慢性肝病和癌症的主要原因。HBV感染的病毒基因组感知和逃避先天免疫反应的机制仍然知之甚少。近年来，环状GMP-AMP合成酶（cyclic GMP-AMP synthase, cGAS）被鉴定为DNA传感器。在本研究中，我们旨在探讨cGAS在感知HBV感染中的功能作用，并阐明病毒逃避的机制。我们在感染性细胞培养模型、原代人肝细胞和hbv感染的人肝嵌合小鼠中进行了功能研究，包括功能丧失和功能获得实验，并结合cGAS效应基因表达谱。本研究表明，cGAS在人肝脏、原代人肝细胞和人肝嵌合小鼠中均有表达。虽然在肝癌细胞系和原代人肝细胞中以cgas依赖的方式感知裸露的松弛环状HBV DNA，但在HBV感染期间，宿主细胞对病毒核酸的识别被取消，这表明可能在基因组包装到病毒衣壳时逃逸。虽然肝细胞cGAS通路具有功能活性，如功能获得性研究中病毒cccDNA水平的降低所示，但HBV感染在细胞培养模型和人源化小鼠中抑制了cGAS的表达和功能。HBV利用多种策略来逃避cGAS及其效应通路的感知和抗病毒活性。
Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic GMP-AMP synthase (cGAS) was identified as a DNA sensor. In this study, we aimed to investigate the functional role of cGAS in sensing of HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss- and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes and HBV-infected human liver chimeric mice. Here we show that cGAS is expressed in the human liver, primary human hepatocytes and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral cccDNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.
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影响因子：
13.5
作者：
Israelow, Benjamin;Narbus, Christopher M.;Sourisseau, Marion;Evans, Matthew J.
通讯作者：
Evans, Matthew J.
影响因子：
13.5
作者：
Fletcher, Simon P.;Chin, Daniel J.;Ji, Yongmei;Iniguez, A. Leonardo;Taillon, Bruce;Swinney, David C.;Ravindran, Palanikumar;Cheng, Donavan T.;Bitter, Hans;Lopatin, Uri;Ma, Han;Klumpp, Klaus;Menne, Stephan
通讯作者：
Menne, Stephan
影响因子：
5.9
作者：
Levrero, Massimo;Testoni, Barbara;Zoulim, Fabien
通讯作者：
Zoulim, Fabien
影响因子：
5.4
作者：
Dansako, Hiromichi;Ueda, Youki;Kato, Nobuyuki
通讯作者：
Kato, Nobuyuki
使用Claudin-1靶向单克隆抗体的人源化小鼠中持续性丙型肝炎病毒感染的清除。
影响因子：
46.9
作者：
Mailly, Laurent;Xiao, Fei;Lupberger, Joachim;Wilson, Garrick K.;Aubert, Philippe;Duong, Franois H. T.;Calabrese, Diego;Leboeuf, Celine;Fofana, Isabel;Thumann, Christine;Bandiera, Simonetta;Luergehetmann, Marc;Volz, Tassilo;Davis, Christopher;Harris, Helen J.;Mee, Christopher J.;Girardi, Erika;Chane-Woon-Ming, Beatrice;Ericsson, Maria;Fletcher, Nicola;Bartenschlager, Ralf;Pessaux, Patrick;Vercauteren, Koen;Meuleman, Philip;Villa, Pascal;Kaderali, Lars;Pfeffer, Sebastien;Heim, Markus H.;Neunlist, Michel;Zeisel, Mirjam B.;Dandri, Maura;McKeating, Jane A.;Robinet, Eric;Baumert, Thomas F.
通讯作者：
Baumert, Thomas F.