The RNA Sensor RIG-I Dually Functions as an Innate Sensor and Direct Antiviral Factor for Hepatitis B Virus

Sato, Seiichi; Li, Kai; Kameyama, Takeshi; Hayashi, T.; Ishida, Yuji; Murakami, Shuko; Watanabe, Tsunamasa; Iijima, Sayuki; Sakurai, Yasuhisa; Watashi, Koichi; Tsutsumi, Susumu; Sato, Yusuke; Akita, Hidetaka; Wakita, Takaji; Rice, Charles M.; Harashima, Hideyoshi; Kohara, Michinori; Tanaka, Yasuhito; Takaoka, Akinori

doi:10.1016/j.immuni.2014.12.016

Cited by 371 publications

(374 citation statements)

References 48 publications

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“…However, several published studies have recently investigated and characterized HBV infection in vitro models and have provided evidence for activation of innate immune pathways (25,30). We therefore endeavored to investigate this by focusing on very early time points after simulation with HBV and DNA-driven innate immune pathways that may play a role in HBV infection.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Yoneda

Hyun

Jakubski

et al. 2016

The Journal of Immunology

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Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA- and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation–associated gene 5 and NF-κB–dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus–host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Yoneda

Hyun

Jakubski

et al. 2016

The Journal of Immunology

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“…Retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen (MDA)-5 are cytosolic molecules that sense double-stranded (ds) RNA as a virus replicative intermediate that subsequently activates the interferon regulatory transcription factor-3 (IRF-3) and NF-kappaB (NF-jB) pathways [20]. The 5 0 -e region of pregenomic HBV RNA has recently been reported to be recognizable by RIG-I in hepatocytes, which subsequently stimulates IFN-k release [21]. RIG-I was also found to exert a direct suppressive effect on HBV replication by interfering with the binding of HBV polymerase to pregenomic RNA [21].…”

Section: Pattern Recognition Receptors In Hbv Infectionmentioning

confidence: 99%

“…The 5 0 -e region of pregenomic HBV RNA has recently been reported to be recognizable by RIG-I in hepatocytes, which subsequently stimulates IFN-k release [21]. RIG-I was also found to exert a direct suppressive effect on HBV replication by interfering with the binding of HBV polymerase to pregenomic RNA [21]. To date, limited information is available regarding which HBV components stimulate relevant PAMP receptors.…”

Section: Pattern Recognition Receptors In Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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“…Human hepatitis B virus (HBV) has its ability to escape the host immune system. [16][17][18] Here, we found that Rubicon can be induced by infection by viruses such as HBV, enterovirus 71 (EV71), influenza A virus (IAV) and vesicular stomatitis virus (VSV) and was a negative regulator for distributed IRF3 activation, IFN induction, and cellular antiviral response. Rubicon interacted with NEMO and suppressed TBK1 phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Inducible Rubicon facilitates viral replication by antagonizing interferon production

et al. 2017

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The RUN domain Beclin-1-interacting cysteine-rich-containing (Rubicon) protein is involved in the maturation step of autophagy and the endocytic pathway as a Beclin-1-binding partner, but little is known regarding the role of Rubicon during viral infection. Here, we performed functional studies of the identified target in interferon (IFN) signaling pathways associated with Rubicon to elucidate the mechanisms of viral resistance to IFN. The Rubicon protein levels were elevated in peripheral blood mononuclear cells, sera and liver tissues from patients with hepatitis B virus (HBV) infection relative to those in healthy individuals. Assays of the overexpression and knockdown of Rubicon showed that Rubicon significantly promoted HBV replication. In addition, Rubicon knockdown resulted in the inhibition of enterovirus 71, influenza A virus and vesicular stomatitis virus. The expression o0f Rubicon led to the suppression of virus-induced type-I interferon (IFN-α and IFN-β) and type-III interferon (IFN-λ1). Translocation of activated IRF3 and IRF7 from the cytoplasm to the nucleus was involved in this process, and the NF-κB essential modulator (NEMO), a key factor in the IFN pathway, was the target with which Rubicon interacted. Our results reveal a previously unrecognized function of Rubicon as a virus-induced protein that binds to NEMO, leading to the inhibition of type-I interferon production. Rubicon thus functions as an important negative regulator of the innate immune response, enhances viral replication and may play a role in viral immune evasion.

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The RNA Sensor RIG-I Dually Functions as an Innate Sensor and Direct Antiviral Factor for Hepatitis B Virus

Cited by 371 publications

References 48 publications

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Host–virus interactions in hepatitis B and hepatitis C infection

Inducible Rubicon facilitates viral replication by antagonizing interferon production

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