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Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response.

ABSTRACT: Although fish possess an efficient interferon (IFN) system to defend against aquatic virus infection, grass carp reovirus (GCRV) still causes hemorrhagic disease in grass carp. To date, GCRV's strategy for evading the fish IFN response is still unknown. Here, we report that GCRV VP41 inhibits fish IFN production by suppressing the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA). First, the activation of the IFN promoter (IFNpro) stimulated by mitochondrial antiviral signaling protein (MAVS) and MITA was decreased by the overexpression of VP41, whereas such activation induced by TANK-binding kinase 1 (TBK1) was not affected. Second, VP41 was colocalized in the cellular endoplasmic reticulum (ER) and associated with MITA. Furthermore, as a phosphorylation substrate of TBK1, VP41 significantly decreased the phosphorylation of MITA. Truncation assays indicated that the transmembrane (TM) region of VP41 was indispensable for the suppression of IFNpro activity. Finally, after infection with GCRV, VP41 blunted the transcription of host IFN and facilitated viral RNA synthesis. Taken together, our findings suggest that GCRV VP41 prevents the fish IFN response by attenuating the phosphorylation of MITA for viral evasion.IMPORTANCE MITA is thought to act as an adaptor protein to facilitate the phosphorylation of IRF3 by TBK1 upon viral infection, and it plays a critical role in innate antiviral responses. Here, we report that GCRV VP41 colocalizes with MITA at the ER and reduces MITA phosphorylation by acting as a decoy substrate of TBK1, thus inhibiting IFN production. These findings reveal GCRV's strategy for evading the host IFN response for the first time.

SUBMITTER: Lu LF

PROVIDER: S-EPMC5487562 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response.

Lu Long-Feng LF Li Shun S Wang Zhao-Xi ZX Du Si-Qi SQ Chen Dan-Dan DD Nie Pin P Zhang Yong-An YA

Journal of virology 20170626 14

Although fish possess an efficient interferon (IFN) system to defend against aquatic virus infection, grass carp reovirus (GCRV) still causes hemorrhagic disease in grass carp. To date, GCRV's strategy for evading the fish IFN response is still unknown. Here, we report that GCRV VP41 inhibits fish IFN production by suppressing the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA). First, the activation of the IFN promoter (IFNpro) stimulated by mitochondrial antivir ...[more]

PMID: 28446676

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Project description:BackgroundThe grass carp hemorrhagic disease caused by the grass carp reovirus (GCRV) is a major disease that hampers the development of grass carp aquaculture. The mechanism underlying GCRV pathogenesis and hemorrhagic symptoms is still unknown. MicroRNAs (miRNAs) are key regulators involved in various biological processes. The aim of this study was to identify conserved and novel miRNAs in grass carp in response to GCRV infection, as well as attempt to reveal the mechanism underlying GCRV pathogenesis and hemorrhagic symptoms.ResultsGrass carp were infected with GCRV, and spleen samples were collected at 0 (control), 1, 3, 5, 7, and 9 days post-infection (dpi). These samples were used to construct and sequence small RNA libraries. A total of 1208 miRNAs were identified, of which 278 were known miRNAs and 930 were novel miRNAs. Thirty-six miRNAs were identified to exhibit differential expression when compared with the control, and 536 target genes were predicted for the 36 miRNAs. GO and KEGG enrichment analyses of these target genes showed that many of the significantly enriched terms were associated with immune response, blood coagulation, hemostasis, and complement and coagulation cascades, especially the GO term "blood coagulation" and pathway "complement and coagulation cascades." Ten representative target genes involved in "complement and coagulation cascades" were selected for qPCR analysis, and the results showed that the expression patterns of these target genes were significantly upregulated at 7 dpi, suggesting that the pathway "complement and coagulation cascades" was strongly activated.ConclusionConserved and novel miRNAs in response to GCRV infection were identified in grass carp, of which 278 were known miRNAs and 930 were novel miRNAs. Many of the target genes involved in immune response, blood coagulation, hemostasis, and complement and coagulation cascades. Strong activation of the pathway "complement and coagulation cascades" may have led to endothelial-cell and blood-cell damage and hemorrhagic symptoms. The present study provides a new insight into understanding the mechanism underlying GCRV pathogenesis and hemorrhagic symptoms.

Project description:BackgroundMyxovirus resistance (Mx) proteins are crucial effectors of the innate antiviral response against a wide range of viruses, mediated by the type I interferon (IFN-I) signaling pathway. However, the antiviral activity of Mx proteins is diverse and complicated in different species.Methodology/principal findingsIn the current study, two novel Mx genes (CiMx1 and CiMx3) were identified in grass carp (Ctenopharyngodon idella). CiMx1 and CiMx3 proteins exhibit high sequence identity (92.1%), and low identity with CiMx2 (49.2% and 49.5%, respectively) from the GenBank database. The predicted three-dimensional (3D) structures are distinct among the three isoforms. mRNA instability motifs also display significant differences in the three genes. The spatial and temporal expression profiles of three C. idella Mx genes and the IFN-I gene were investigated by real-time fluorescence quantitative RT-PCR (qRT-PCR) following infection with grass carp reovirus (GCRV) in vivo and in vitro. The results demonstrated that all the four genes were implicated in the anti-GCRV immune response, that mRNA expression of Mx genes might be independent of IFN-I, and that CIK cells are suitable for antiviral studies. By comparing expression patterns following GCRV challenge or poly(I:C) treatment, it was observed that GCRV blocks mRNA expression of the four genes. To determine the functions of Mx genes, three CiMx cDNAs were cloned into expression vectors and utilized for transfection of CIK cells. The protection conferred by each recombinant CiMx protein against GCRV infection was evaluated. Antiviral activity against GCRV was demonstrated by reduced cytopathic effect, lower virus titer and lower levels of expressed viral transcripts. The transcription of IFN-I gene was also monitored.Conclusions/significanceThe results indicate all three Mx genes can suppress replication of grass carp reovirus and over-expression of Mx genes mediate feedback inhibition of the IFN-I gene.

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Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response.

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Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response.

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