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Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus.

ABSTRACT: Spring viraemia of carp virus (SVCV) causes high morality in several economically important cyprinid fishes, but there is no approved therapy up to now. To address the urgent need for therapeutics to combat SVCV infection, we investigated the anti-SVCV activities of 12 natural compounds and 7 common antiviral agents using epithelioma papulosum cyprini (EPC) cells in this study. From the 19 compounds, we identified arctigenin (ARG) has the highest inhibition on SVCV replication, with maximum inhibitory percentage on SVCV > 90%. And the 48 h half maximal inhibitory concentrations (IC₅₀) of ARG on SVCV glycoprotein and nucleoprotein were 0.29 (0.22-0.39) and 0.35 (0.29-0.41) mg/L respectively. In addition, ARG significantly reduced SVCV-induced apoptosis and recovered SVCV-activated caspase-3/8/9 activity. Further, cellular morphological damage induced by SVCV was blocked by ARG treatment. Mechanistically, ARG did not affect SVCV infectivity. Moreover, ARG could not induce reactive oxygen species (ROS) generation, which plays an antiviral role on SVCV. Interestingly, SVCV-induced autophagy which is necessary for virus replication was inhibited by ARG treatment. These results indicated that the inhibition of ARG on SVCV replication was, at least in part, via blocking SVCV-induced autophagy. Taken together, ARG has the potential to work as an agent for protecting economically important fishes against SVCV.

SUBMITTER: Shen YF

PROVIDER: S-EPMC7126542 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus.

Shen Yu-Feng YF Liu Lei L Chen Wei-Chao WC Hu Yang Y Zhu Bin B Wang Gao-Xue GX

Aquaculture. 20170905

Spring viraemia of carp virus (SVCV) causes high morality in several economically important cyprinid fishes, but there is no approved therapy up to now. To address the urgent need for therapeutics to combat SVCV infection, we investigated the anti-SVCV activities of 12 natural compounds and 7 common antiviral agents using epithelioma papulosum cyprini (EPC) cells in this study. From the 19 compounds, we identified arctigenin (ARG) has the highest inhibition on SVCV replication, with maximum inhi ...[more]

PMID: 32287458

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Project description:Spring viremia of carp virus (SVCV) is a highly pathogenic Vesiculovirus infecting the common carp, yet neither a vaccine nor effective therapies are available to treat spring viremia of carp (SVC). Like all negative-sense viruses, SVCV contains an RNA genome that is encapsidated by the nucleoprotein (N) in the form of a ribonucleoprotein (RNP) complex, which serves as the template for viral replication and transcription. Here, the three-dimensional (3D) structure of SVCV RNP was resolved through cryo-electron microscopy (cryo-EM) at a resolution of 3.7 Å. RNP assembly was stabilized by N and C loops; RNA was wrapped in the groove between the N and C lobes with 9 nt nucleotide per protomer. Combined with mutational analysis, our results elucidated the mechanism of RNP formation. The RNA binding groove of SVCV N was used as a target for drug virtual screening, and it was found suramin had a good antiviral effect. This study provided insights into RNP assembly, and anti-SVCV drug screening was performed on the basis of this structure, providing a theoretical basis and efficient drug screening method for the prevention and treatment of SVC. IMPORTANCE Aquaculture accounts for about 70% of global aquatic products, and viral diseases severely harm the development of aquaculture industry. Spring viremia of carp virus (SVCV) is the pathogen causing highly contagious spring viremia of carp (SVC) disease in cyprinids, especially common carp (Cyprinus carpio), yet neither a vaccine nor effective therapies are available to treat this disease. In this study, we have elucidated the mechanism of SVCV ribonucleoprotein complex (RNP) formation by resolving the 3D structure of SVCV RNP and screened antiviral drugs based on the structure. It is found that suramin could competitively bind to the RNA binding groove and has good antiviral effects both in vivo and in vitro. Our study provides a template for rational drug discovery efforts to treat and prevent SVCV infections.

Project description:Spring viraemia of carp (SVC) is a fatal viral disease for cyprinid fish, which is caused by spring viraemia of carp virus (SVCV). To date, no SVC outbreak has been reported in China. Between 1998 and 2002, outbreaks of SVC were reported in ornamental and wild fish in Europe and America, imported from multiple sources including China. Based on phylogenetic analysis, the viral strain isolated from America was shown to be originated from Asia. These outbreaks not only resulted in huge economic losses, but also raise an interesting question as to whether SVCV really exists in China and if so, is it responsible for SVC outbreaks? From 2002 to 2006, we screened 6700 samples from ornamental fish farms using the cell culture method of the Office International des Epizooties (OIE), and further verified the presence of SVCV by ELISA and real-time quantitative RT-PCR. Two infected samples were found and the complete genome of SVCV was sequenced from one of the isolates, termed SVCV-C1. Several unique hallmarks of SVCV-C1 were identified, including six amino acid (KSLANA) insertion in the viral RNA-dependent RNA polymerase (L) protein and ten nucleotide insertion in the region between glycoprotein (G) and L genes in European SVCV strains. Phylogenetic tree analysis of the full-length G protein of selected SVCV isolates from the United Kingdom and United States revealed that G proteins could be classified into Ia and Id sub genogroups. The Ia sub genogroup can be further divided into newly defined sub genogroups Ia-A and Ia-B. The isolates derived from the United States and China including the SVCV-C1 belongs to in the Ia-A sub genogroup. The SVCV-C1 G protein shares more than 99% homology with the G proteins of the SVCV strains from England and the United States, making it difficult to compare their pathogenicity. Comparison of the predicted three-dimensional structure based on the published G protein sequences from five SVCV strains revealed that the main differences were in the loops of the pleckstrin homology domains. Since SVCV is highly pathogenic, we speculate that SVC may therefore pose a serious threat to farmed cyprinid fish in China.

Project description:β-glucan has been used as immunostimulant for fish. However, the effect of yeast β-glucan on viral infections has been less studied in fish. In this study, we investigated the effects of β-glucan on the resistance of zebrafish against spring viraemia of carp virus (SVCV) and elucidated the underlying mechanisms. Zebrafish were fed with a control diet or diet supplemented with 0.01% and 0.025% β-glucan for 2 weeks, and were challenged by SVCV. Zebrafish embryonic fibroblast (ZF4) cells were treated with 5 μg/mL β-glucan and were infected by SVCV. We further investigated the effect of β-glucan on autophagy level post SVCV infection. The intestinal microbiota was evaluated by 16S rRNA gene pyrosequencing. Results showed that dietary supplementation of 0.025% β-glucan significantly increased survival rate of zebrafish compared with control group after SVCV challenge (P < 0.05). Dietary β-glucan significantly increased the expression of genes related to type I IFN antiviral immune pathway in the spleen of zebrafish after viral infection, including type I IFN genes (ifnφ1, ifnφ2, ifnφ3), IFN-stimulated genes (mxb, mxc), as well as other genes involved in the IFN signaling pathway, including tlr7, rig1, mavs, irf3 and irf7. Morpholino knockdown of type I IFN receptors dampened the antiviral effect of β-glucan in zebrafish larvae, indicating that β-glucan-mediated antiviral function was at least partially dependent on IFN immune response. Furthermore, β-glucan can inhibit the replication of SVCV in ZF4 cells. However, β-glucan did not stimulate type I IFN antiviral response in ZF4 cells, and the antiviral effect of β-glucan in ZF4 was independent of Myd88. Interestingly, β-glucan induced autophagy in ZF4 cells after SVCV infection. Inhibition of autophagy blocked the antiviral effect of β-glucan in ZF4 cells. Lastly, dietary β-glucan changed the composition of intestinal microbiota in zebrafish, with reduced abundance of Proteobacteria and an enrichment of Fusobacteria and Firmicutes. To sum up, our results indicate that the β-glucan enhanced resistance of zebrafish against SVCV and the mechanism involved stimulation of type I IFN antiviral immune response of fish after viral infection.

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Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus.

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Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus.

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