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.

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Journal Hepatology
Xu, L, Wang, W, Li, Y. (Yunlong), Zhou, X, Yin, Y, Wang, Y, … Pan, Q. (2017). RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus regardless of interferon production. Hepatology. doi:10.1002/hep.29105