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Journal article
Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus
Antimicrobial agents and chemotherapy, v 61(10)
22 Sep 2017
PMID: 28717041
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Induction of interferon and proinflammatory cytokines is a hallmark of the infection of many different viruses. However, hepatitis B virus (HBV) does not elicit a detectable cytokine response in infected hepatocytes. In order to investigate the molecular mechanism underlying the innate immune evasion, a functional cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway was reconstituted in a human hepatoma cell line supporting tetracycline-inducible HBV replication. It was demonstrated that induction of HBV replication neither activated nor inhibited this cytosolic DNA sensing pathway. However, human hepatoma cells, as well as immortalized mouse hepatocytes, express low levels of STING, which upon activation by cGAMP, the natural ligand of STING, led to induction of a proinflammatory cytokine response. Treatment of immortalized mouse hepatocytes supporting HBV replication with either cGAMP or a small molecule pharmacologic STING agonist significantly reduced viral DNA in a STING- and Janus kinase 1-dependent manner. Moreover, cGAMP treatment was able to induce inflammatory cytokine gene expression and inhibit the transcription of covalently closed circular DNA in HBV-infected human hepatoma cells expressing sodium taurocholate cotransporting polypeptide, an essential receptor for HBV infection of hepatocytes. The studies reported here and previously (F. Guo et al., Antimicrob Agents Chemother 59:1273–1281, 2015, https://doi.org/10.1128/AAC.04321-14 ) thus support the notion that pharmacological activation of STING in macrophages and hepatocytes induces host innate responses that can efficiently control HBV replication. Hence, despite not playing a significant role in host innate immune response to HBV infection of hepatocytes, STING is potentially a valuable target for immunotherapy of chronic hepatitis B.
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Details
- Title
- Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus
- Creators
- Fang Guo - Baruch S. Blumberg InstituteLiudi Tang - Drexel UniversitySainan Shu - Huazhong University of Science and TechnologyMohit Sehgal - Baruch S. Blumberg InstituteMuhammad Sheraz - Drexel UniversityBowei Liu - Zhengzhou UniversityQiong Zhao - Baruch S. Blumberg InstituteJunjun Cheng - Baruch S. Blumberg InstituteXuesen Zhao - Baruch S. Blumberg Institute, Doylestown, Pennsylvania, USATianlun Zhou - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg Institute
- Publication Details
- Antimicrobial agents and chemotherapy, v 61(10)
- Publisher
- American Society for Microbiology
- Number of pages
- 15
- Grant note
- AI113267 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000411481800017
- Scopus ID
- 2-s2.0-85029754603
- Other Identifier
- 991019168994404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy