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

Abstract

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).

Type III Interferons in Viral Infection and Antiviral Immunity

“…Due to the partially overlapping signaling pathways (RIG-I, MDA5 and MAVS) mediated by type I and type III IFNs, the paradoxical immune activities might be performed by the two types of IFN. Regardless of IFN subtypes, RIG-I activates two distinct categories of ISGs, one JAK-STAT-dependent and the other JAK-STAT-independent, which coordinately contribute to the antiviral immune response to HEV infection [92]. However, persistent activation of the JAK-STAT-dependent signaling pathway enables HEV-infected cells to resist exogenous IFN treatment, while the depletion of IFN-λ receptors or MAVS (mitochondria antiviral signaling protein) resorts to the antiviral immune response induced by IFN, suggesting that the persistent presence of IFN-λ benefits the establishment of HEV infection [93].…”

Beyond sensing: Retinoic acid inducible gene‐I (RIG‐I) continues to expand its antiviral effector functions

“…(4) RIG‐I induces STAT1 phosphorylation independent of IFN induction. (5) RIG‐I induces ISG production independent of IRF3/7 and STAT1 signaling, as describes by Xu et al This action may be mediated by MAVS and NF‐κB or potentially other transcription factors.…”

“…On the surface, this article shows that RIG‐I, an RNA helicase and pathogen recognition receptor, controls HEV infection in human cells . While this finding has implications for clinical treatment of patients with HEV by targeting RIG‐I with activator molecules, the authors elucidate that this outcome is mediated independently of IFN .…”

“…While RIG‐I can also serve as an antiviral effector gene to bind to viral RNA and block RNA/protein associations, it is widely recognized for trigging this innate immune antiviral signaling cascade as a result of PAMP recognition and binding . Xu and colleagues now reveal a role for RIG‐I in mediating innate immune effector actions against HEV that show roles for RIG‐I in IFN‐independent innate immunity. Remarkably, RIG‐I is observed to drive the expression of a subset of ISGs independently of IRF3, IRF7, and IFN but requiring NF‐κB actions, thus providing evidence for a novel RIG‐I‐directed innate immune effector response pathway in hepatocytes (the target cell of HEV infection) that uncouples IRF and NF‐κB signaling programs to operate outside of the canonical IRF/IFN/ISG innate immune effector pathway (Fig.…”

“…Other groups have shown that RIG‐I overexpression, followed by its activation by viral RNA transfection or actual virus infection can induce IRF3 activation and IFN and ISG expression in hepatoma cells and hepatocytes during infection by hepatitis C virus, another liver‐tropic virus (reviewed in Loo and Gale). Now Xu et al report that overexpression of RIG‐I and activation of its signaling actions through transfection of cells with PAMP RNA ligand fails to induce IFN production . This observation is validated through bioassays that include assessment of a sensitive IFN‐induced promoter‐luciferase reporter gene (ISRE‐Luc)—in this case when RIG‐I was expressed and activated the ISRE‐Luc promoter was highly induced and ISGs were expressed, but no IFN was produced when RIG‐I was overexpressed and activated .…”