学科主题临床医学
STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus
Guo, Fang1; Han, Yanxing2,3,4; Zhao, Xuesen1,5; Wang, Jianghua6; Liu, Fei1; Xu, Chunxiao1; Wei, Lai6; Jiang, Jian-Dong2,3,4; Block, Timothy M.1,5; Guo, Ju-Tao1; Chang, Jinhong1
刊名ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
2015-02-01
DOI10.1128/AAC.04321-14
59期:2页:1273-1281
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Microbiology ; Pharmacology & Pharmacy
研究领域[WOS]Microbiology ; Pharmacology & Pharmacy
关键词[WOS]NONPARENCHYMAL LIVER-CELLS ; MOUSE MODEL ; 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID ; VIRAL-HEPATITIS ; TRANSGENIC MICE ; INFECTION ; REPLICATION ; HBV ; RECOVERY ; NUCLEOCAPSIDS
英文摘要

Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

语种英语
WOS记录号WOS:000348610000064
项目编号R01AI113267 ; 81321004 ; 2012ZX09301002-003/006 ; BZ0150 ; 2012CB911103
资助机构NIH ; Hepatitis B Foundation from the Commonwealth of Pennsylvania ; National Natural Science Foundation of China ; State Mega Programs ; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study ; 973 project
引用统计
被引频次:34[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/61237
专题北京大学第二临床医学院_北京大学肝病研究所
作者单位1.Drexel Univ, Coll Med, Dept Microbiol & Immunol, Inst Biotechnol & Virol Res, Doylestown, PA 18902 USA
2.Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100730, Peoples R China
3.Peking Union Med Coll, Beijing 100021, Peoples R China
4.Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China
5.Hepatitis B Fdn, Baruch S Blumberg Inst, Doylestown, PA USA
6.Peking Univ, Peoples Hosp, Inst Hepatol, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Guo, Fang,Han, Yanxing,Zhao, Xuesen,et al. STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2015,59(2):1273-1281.
APA Guo, Fang.,Han, Yanxing.,Zhao, Xuesen.,Wang, Jianghua.,Liu, Fei.,...&Chang, Jinhong.(2015).STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,59(2),1273-1281.
MLA Guo, Fang,et al."STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 59.2(2015):1273-1281.
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