Dataset Information

Reovirus inhibits interferon production by sequestering IRF3 into viral factories.

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 ?NS 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.

SUBMITTER: Stanifer ML

PROVIDER: S-EPMC5589761 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reovirus inhibits interferon production by sequestering IRF3 into viral factories.

Stanifer Megan L ML Kischnick Christian C Rippert Anja A Albrecht Dorothee D Boulant Steeve S

Scientific reports 20170907 1

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 evad ...[more]

PMID: 28883463

Similar Datasets

Project description:UnlabelledPorcine epidemic diarrhea virus (PEDV), a porcine enteropathogenic coronavirus, causes lethal watery diarrhea in piglets and results in large economic losses in many Asian and European countries. A large-scale outbreak of porcine epidemic diarrhea occurred in China in 2010, and the virus emerged in the United States in 2013 and spread rapidly, posing significant economic and public health concerns. Previous studies have shown that PEDV infection inhibits the synthesis of type I interferon (IFN), and viral papain-like protease 2 has been identified as an IFN antagonist. In this study, we found that the PEDV-encoded nucleocapsid (N) protein also inhibits Sendai virus-induced IFN-β production, IFN-stimulated gene expression, and activation of the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB. We also found that N protein significantly impedes the activation of the IFN-β promoter stimulated by TBK1 or its upstream molecules (RIG-I, MDA5, IPS-1, and TRAF3) but does not counteract its activation by IRF3. A detailed analysis revealed that the PEDV N protein targets TBK1 by direct interaction and that this binding sequesters the association between TBK1 and IRF3, which in turn inhibits both IRF3 activation and type I IFN production. Together, our findings demonstrate a new mechanism evolved by PEDV to circumvent the host's antiviral immunity.ImportancePEDV has received increasing attention since the emergence of a PEDV variant in China and the United States. Here, we identify nucleocapsid (N) protein as a novel PEDV-encoded interferon (IFN) antagonist and demonstrate that N protein antagonizes IFN production by sequestering the interaction between IRF3 and TBK1, a critical step in type I IFN signaling. This adds another layer of complexity to the immune evasion strategies evolved by this economically important viral pathogen. An understanding of its immune evasion mechanism may direct us to novel therapeutic targets and more effective vaccines against PEDV infection.

Project description:African swine fever is a devastating disease of swine caused by African swine fever virus (ASFV). The pathogenesis of the disease remains largely unknown, leaving the spread of the disease uncontrolled in many countries and regions. Here, we identified E120R, a structural protein of ASFV, as a key virulence factor and late-phase-expressed protein of the virus. E120R revealed an activity to suppress the host antiviral response through blocking beta interferon (IFN-β) production, and the amino acids (aa) at sites 72 and 73 (amino acids 72-73) in the C-terminal domain were essential for this function. E120R interacted with interferon regulatory factor 3 (IRF3) and interfered with the recruitment of IRF3 to TANK-binding kinase 1 (TBK1), which in turn suppressed IRF3 phosphorylation, decreasing interferon production. A recombinant mutant ASFV was further constructed to confirm the claimed mechanism. The ASFV lacking the complete E120R region could not be rescued, whereas the virus could tolerate the deletion of the 72nd and 73rd residues in E120R (ASFV E120R-Δ72-73aa). ASFV E120R with the two-amino-acid deletion failed to interact with IRF3 during ASFV E120R-Δ72-73aa infection, and the viral infection activated IRF3 phosphorylation highly and induced more robust type I interferon production than its parental ASFV. An unbiased transcriptome-wide analysis of gene expression also confirmed that considerably more IFN-stimulated genes (ISGs) were detected in ASFV E120R-Δ72-73aa-infected porcine alveolar macrophages (PAMs) than in wild-type ASFV-infected PAMs. Together, our findings have identified a novel mechanism evolved by ASFV to inhibit the host antiviral response, and they provide a new target for guiding the development of ASFV live-attenuated vaccine. IMPORTANCE African swine fever is a highly contagious animal disease affecting the pig industry worldwide, which has brought enormous economic losses. Infection by the causative agent, African swine fever virus (ASFV), causes severe immunosuppression during viral infection, contributing to serious clinical manifestations. Therefore, identification of the viral proteins involved in immunosuppression is critical for ASFV vaccine design and development. Here, for the first time, we demonstrated that E120R protein, a structural protein of ASFV, played an important role in suppression of interferon regulatory factor 3 (IRF3) phosphorylation and type I interferon production by binding to IRF3 and blocking the recruitment of IRF3 to TANK-binding kinase 1 (TBK1). Deletion of the crucial binding sites in E120R critically increased the interferon response during ASFV infection. This study explored a novel antagonistic mechanism of ASFV, which is critical for guiding the development of ASFV live-attenuated vaccines.

Dataset Information

Reovirus inhibits interferon production by sequestering IRF3 into viral factories.

Publications

Reovirus inhibits interferon production by sequestering IRF3 into viral factories.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets