Journal article
STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus
Antimicrobial agents and chemotherapy, Vol.59(2), pp.1273-1281
27 Jan 2015
PMCID: PMC4335851
PMID: 25512416
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus
- Creators
- Fang Guo - Drexel UniversityYanxing Han - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaXuesen Zhao - Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USAJianghua Wang - Peking University People's HospitalFei Liu - Drexel UniversityChunxiao Xu - Drexel UniversityLai Wei - Peking University People's HospitalJian-Dong Jiang - Chinese Academy of Medical Sciences & Peking Union Medical CollegeTimothy M Block - Baruch S. Blumberg InstituteJu-Tao Guo - Drexel UniversityJinhong Chang - Drexel University
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.59(2), pp.1273-1281
- Publisher
- American Society for Microbiology
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Identifiers
- 991019167553904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy