Bovine viral diarrhea virus NS4B protein interacts with 2CARD of MDA5 domain and negatively regulates the RLR-mediated IFN-β production

Shan, Yue; Tong, Zhao; Ma, Jingyun; Liu, Yü; Zhang, Zecai; Wu, Chenhua; Huang, Weixin; Liu, Siyu; Chen, Nannan; Siyu, Su; Bai, Tongtong; Huang, Jiansheng; Biaohui, Bai; Jin, Xin; Zhou, Youwen; Zhang, Zhu

doi:10.1016/j.virusres.2021.198471

Cited by 13 publications

(9 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NS4B is a well-known IFN inhibitor in different flaviviruses, mediating the evasion of both IFN production and signaling [7]. In fact, on one hand, yellow fever virus (YFV), hepatitis C virus (HCV), duck Tembusu virus (TMUV) and bovine viral diarrhea virus (BVDV) NS4B have been reported to block the RIG-I /MDA-5 pathway of IFN production [10][11][12][13][14]. On the other hand, dengue virus (DENV), West Nile virus (WNV) and YFV NS4B were shown to inhibit the IFN signaling pathway by suppressing the phosphorylation and nuclear transport of STAT1/STAT2 [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation

Fanunza

Grandi

Quartu

et al. 2021

Viruses

View full text Add to dashboard Cite

The evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antagonist of the IFN signaling cascade. Firstly, we reported the genomic characterization of NS4B isolated from a strain of the 2016 outbreak, ZIKV Brazil/2016/INMI1, and we predicted its membrane topology. Secondly, we analyzed its phylogenetic correlation with other flaviviruses, finding a high similarity with dengue virus 2 (DEN2) strains; in particular, the highest conservation was found when NS4B was aligned with the IFN inhibitory domain of DEN2 NS4B. Hence, we asked whether ZIKV NS4B was also able to inhibit the IFN signaling cascade, as reported for DEN2 NS4B. Our results showed that ZIKV NS4B was able to strongly inhibit the IFN stimulated response element and the IFN-γ-activated site transcription, blocking IFN-I/-II responses. mRNA expression levels of the IFN stimulated genes ISG15 and OAS1 were also strongly reduced in presence of NS4B. We found that the viral protein was acting by suppressing the STAT1 phosphorylation and consequently blocking the nuclear transport of both STAT1 and STAT2.

show abstract

Section: Introductionmentioning

confidence: 99%

INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation

Fanunza

Grandi

Quartu

et al. 2021

Viruses

View full text Add to dashboard Cite

show abstract

“…The second mechanism by which BVDV inhibits IFN-α/β is that of the non-structural protein N pro , which acts as a protease capable of degrading IRF3 and preventing its binding to DNA ( 16 ). Recent research demonstrated that the interaction of the BVDV NS4B non-structural protein with the two-caspase activation and recruitment domains region in the melanoma differentiation-associated protein 5 domain of the RIG-I-like receptor signalling pathway negatively regulates IFN-β and significantly inhibits the phosphorylation of IRF3 ( 20 ). The significantly lower IRF3 expression in the untreated BVDV-infected cell group than in the control group (without BVDV and drug) at 24 h in our study is consistent with reported findings ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Matrine and icariin can inhibit bovine viral diarrhoea virus replication by promoting type I interferon response in vitro

Cai,

Shen,

Tian

et al. 2024

Journal of Veterinary Research

View full text Add to dashboard Cite

Introduction Bovine viral diarrhoea virus (BVDV) can cause diarrhoea (BVD) in an animal herd, leading to heavy economic losses. There are limited drugs available for treating and controlling BVD. This research aims to investigate the antiviral and immunoregulatory effects of two traditional Chinese herb extracts against BVDV infection. The extracts are matrine and icariin, which have been proved to have immunostimulant and antiviral effects. Material and Methods A cell counting kit-8 assay was used to analyse the toxicity of matrine and icariin to Madin–Darby bovine kidney (MDBK) cells. The model of MDBK cells infected with BVDV was utilised to uncover the antiviral mechanism of matrine and icariin, which along with their immunoregulatory ability was evaluated by quantitative reverse-transcription PCR and ELISA. Results The results showed that matrine and icariin can significantly inhibit the gene expression level of the BVDV 5′ untranslated region through various pathways. Both matrine and icariin can statistically upregulate the gene expression level of interferon alpha, interferon beta (IFN-β), toll-like receptor 3, retinoic acid–inducible gene I and interferon regulatory factor 3, and raise the concentration of IFN-β after BVDV infection. Conclusion This study proves that both matrine and icariin have inhibitory effects on BVDV replication by activating IFN production and the IFN signalling pathway. The finding is promising and should open up the possibility of larger-scale in vitro research followed by in vivo experiments evaluating matrine and icariin as therapeutic agents in BVD cases.

show abstract

“…The readaptation of this strain through the passage in pigs highlighted that the manipulation of the spread was mainly based on the E2 substitution while, the NS4B substitutions was required for viral replication (34). Recently, it has been shown that BVDV-NS4B suppresses interferon-β production by interfering with MDA5mediated signaling (37).…”

Section: Discussionmentioning

confidence: 99%

Immunoinformatic prediction of the pathogenicity of bovine viral diarrhea virus genotypes: implications for viral virulence determinants, designing novel diagnostic assays and vaccines development

et al. 2023

View full text Add to dashboard Cite

IntroductionBovine viral diarrhea virus (BVDV) significantly impacts the bovine industries, both dairy and beef sectors. BVDV can infect various domestic and wild animals, most notably cattle. The dynamic variations among BVDV serotypes due to the continuous genetic diversity, especially in BVDV1 (BVDV1), reduce the effectiveness of the currently available vaccines and reduce the specificity/sensitivity of the diagnostic assays. The development of novel, safe, and effective vaccines against BVDV requires deep knowledge of the antigenicity and virulence of the virus. Previous studies on the antigenicity and the virulence of BVDV serotypes have been mainly focused on one or a few BVDV proteins. While however, little is known about the orchestration of all BVDV in the context of viral virulence and immunogenicity. The main aim of the current study was to do a comparative computational evaluation of the immunogenicity, and virulence for all the encoded proteins of both BVDV1 and BVDV2 and their sub-genotypes.MethodsTo achieve this goal, 11,737 protein sequences were retrieved from Virus Pathogen Resource. The analysis involved a total of 4,583 sequences after the removal of short sequences and those with unknown collection time. We used the MP3 tool to map the pathogenic proteins across different BVDV strains. The potential protective and the epitope motifs were predicted using the VaxiJen and EMBOSS antigen tools, respectively.Results and discussionThe virulence prediction revealed that the NS4B proteins of both BVDV1 and BVDV2 likely have essential roles in BVDV virulence. Similarly, both the capsid (C) and the NS4-A proteins of BVDV1 and the Npro and P7 proteins of BVDV2 are likely important virulent factors. There was a clear trend of increasing predicted virulence with the progression of time in the case of BVDV1 proteins, but that was not the case for the BVDV2 proteins. Most of the proteins of the two BVDV serotypes possess antigens predicted immunogens except Npro, P7, and NS4B. However, the predicted antigenicity of the BVDV1 was significantly higher than that of BVDV2. Meanwhile, the predicted immunogenicity of the immunodominant-E2 protein has been decreasing over time. Based on our predicted antigenicity and pathogenicity studies of the two BVDV serotypes, the sub-genotypes (1a, 1f, 1k, 2a, and 2b) may represent ideal candidates for the development of future vaccines against BVDV infection in cattle. In summary, we identified some common differences between the two BVDV genotypes (BVDV1 and BVDV2) and their sub-genotypes regarding their protein antigenicity and pathogenicity. The data presented here will increase our understanding of the molecular pathogenesis of BVDV infection in cattle. It will also pave the way for developing some novel diagnostic assays and novel vaccines against BVDV in the near future.

show abstract

Bovine viral diarrhea virus NS4B protein interacts with 2CARD of MDA5 domain and negatively regulates the RLR-mediated IFN-β production

Cited by 13 publications

References 36 publications

INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation

INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation

Matrine and icariin can inhibit bovine viral diarrhoea virus replication by promoting type I interferon response in vitro

Immunoinformatic prediction of the pathogenicity of bovine viral diarrhea virus genotypes: implications for viral virulence determinants, designing novel diagnostic assays and vaccines development

Contact Info

Product

Resources

About