RIG‐I is a key antiviral interferon‐stimulated gene against hepatitis E virus regardless of interferon production

Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN‐stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hep...

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Published in:Hepatology (Baltimore, Md.) Md.), 2017-06, Vol.65 (6), p.1823-1839
Main Authors: Xu, Lei, Wang, Wenshi, Li, Yunlong, Zhou, Xinying, Yin, Yuebang, Wang, Yijin, de Man, Robert A., van der Laan, Luc J.W., Huang, Fen, Kamar, Nassim, Peppelenbosch, Maikel P., Pan, Qiuwei
Format: Article
Language:English
Subjects:
Antiviral activity
Cell culture
Cells, Cultured
DEAD Box Protein 58 - genetics
Gene Expression Regulation, Viral
Hepatitis
Hepatitis E - genetics
Hepatitis E - immunology
Hepatitis E virus - genetics
Hepatitis E virus - immunology
Hepatocytes - immunology
Hepatocytes - metabolism
Hepatology
Humans
Immunity, Innate - genetics
Infections
Innate immunity
Interferon
Interferon regulatory factor 1
Interferon regulatory factor 3
Interferon regulatory factor 7
Interferon Regulatory Factor-3 - genetics
Interferon-alpha - immunology
Interferon-alpha - metabolism
Janus kinase
Melanoma
Receptors, Immunologic
Replication
Retinoic acid
Ribonucleic acid
RNA
Sensitivity and Specificity
Signal Transduction - physiology
Transcription
Up-Regulation
Virus Replication - genetics
Virus Replication - immunology
α-Interferon
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Summary:Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN‐stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti‐HEV ISG was further studied. We identified retinoic acid–inducible gene I (RIG‐I), melanoma differentiation–associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti‐HEV ISGs. We found that basal expression of RIG‐I restricts HEV infection. Pharmacological activation of the RIG‐I pathway by its natural ligand 5′‐triphosphate RNA potently inhibits HEV replication. Overexpression of RIG‐I activates the transcription of a wide range of ISGs. RIG‐I also mediates but does not overlap with IFN‐α‐initiated ISG transcription. Although it is classically recognized that RIG‐I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN‐independent antiviral mechanism of RIG‐I in combating HEV infection. We found that activation of RIG‐I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG‐I activated two distinct categories of ISGs, one JAK‐STAT‐dependent and the other JAK‐STAT‐independent, which coordinately contribute to the anti‐HEV activity. Conclusion: We identified RIG‐I as an important anti‐HEV ISG that can be pharmacologically activated; activation of RIG‐I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK‐STAT cascade of IFN signaling. (Hepatology 2017;65:1823‐1839).
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.29105