title: STING agonists induce an innate antiviral immune response against hepatitis B virus.
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.
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China jinhong.chang@drexelmed.edu hanyanxing@imm.ac.cn.
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA jinhong.chang@drexelmed.edu hanyanxing@imm.ac.cn.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy; D007113:Immunity, Innate / Q000187:drug effects; D008565:Membrane Proteins / Q000819:agonists; D051379:Mice; D014779:Virus Replication / Q000187:drug effects; D044004:Xanthones / Q000627:therapeutic use; D000099197:STING Protein
chemical_list: D000998:Antiviral Agents; D008565:Membrane Proteins; D044004:Xanthones; C530855:Sting1 protein, mouse; D000099197:STING Protein; C066668:vadimezan