Reovirus inhibits interferon production by sequestering IRF3 into viral factories

Megan L Stanifer,Anja Rippert,Steeve Boulant,Dorothee Albrecht,Christian Kischnick

doi:10.1038/s41598-017-11469-6

Megan L Stanifer, Anja Rippert + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-11469-6

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Abstract

Upon viral infection, an arms-race between the cellular intrinsic innate immune system and viral replication is established. To win this race, viruses have established multiple strategies to inhibit the cellular response. Mammalian reovirus (MRV) constitutes a great model to study pathogenesis and life cycle of dsRNA viruses. It replicates in the cytosol of infected cells by forming viral induced-replication compartments, or viral factories. Little is known about the strategy used by MRV to evade the cellular intrinsic immune system. In this study, we unraveled that MRV induces a replication-dependent global reduction in interferon-mediated antiviral immune response. We determined that although MRV leads to the activation and phosphorylation of interferon regulatory factor 3 (IRF3), the nuclear translocation of IRF3 was impaired in infected cells. Additionally, we showed that MRV does not degrade IRF3 but sequesters it in cytoplasmic viral factories. We demonstrate that the viral factory matrix protein μNS is solely responsible for the sequestration of IRF3. This finding highlights novel mechanisms used by MRV to interfere with the intrinsic immune system and places the viral factories as not only a replication compartment but as an active strategy participating in immune evasion.

Highlights

From the onset of viral infection, a race between cellular strategies to inhibit viral replication/spread and viral strategies to directly interfere with these cellular mechanisms is initiated
Our previous work determined that Mammalian reoviruses (MRV) intermediate subviral particles (ISVPs) induce a lower immune response during infection of cells compared to their virion counterparts[22]
We show that both MRV virions and ISVPs are sensed by the intrinsic innate immune pathway leading to the activation of interferon regulatory factor 3 (IRF3) by phosphorylation, ISVPs induce a reduced antiviral immune response compared to their virion counterparts

Summary

Introduction

From the onset of viral infection, a race between cellular strategies to inhibit viral replication/spread and viral strategies to directly interfere with these cellular mechanisms is initiated. Upon sensing of viral RNA, RLR proteins form together with the MAVS protein located on the surface of mitochondria and peroxisomes[1] a signaling platform that induces the activation of a complex signaling cascade while TLR3 forms a complex with TRIF, which establishes a similar signaling cascade[2, 3] This signaling leads to the activation of both the NF-κB and the interferon regulatory factor 3 (IRF3) pathways which upon activation translocate in the nucleus where they act as transcription factors to induce the production of interferons (IFNs), a subset of interferon stimulated genes (ISGs), and pro-inflammatory cytokines. Has been suggested that these VFs, by retaining viral constituents (viral nucleic acids and proteins) in a confined environment, act as a protective barrier to avoid sensing by the intrinsic innate immune system. Σ3 protein appears to modulate the type I IFN response by inhibiting the dsRNA-mediated activation of PKR29

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