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Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways

Peste des petits ruminants virus (PPRV), belonging to the genus Morbillivirus in the family Paramyxoviridae, causes severe infectious disease in small ruminants and has been rapidly spreading in many parts of Africa, the Middle East, and Asia. Although vaccination is considered to be an effective me...

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Autores principales: Zhang, Weifeng, Deng, Hualong, Liu, Yanfen, Chen, Shaohong, Liu, You, Zhao, Yuntao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450531/
https://www.ncbi.nlm.nih.gov/pubmed/34552976
http://dx.doi.org/10.3389/fvets.2021.722840
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author Zhang, Weifeng
Deng, Hualong
Liu, Yanfen
Chen, Shaohong
Liu, You
Zhao, Yuntao
author_facet Zhang, Weifeng
Deng, Hualong
Liu, Yanfen
Chen, Shaohong
Liu, You
Zhao, Yuntao
author_sort Zhang, Weifeng
collection PubMed
description Peste des petits ruminants virus (PPRV), belonging to the genus Morbillivirus in the family Paramyxoviridae, causes severe infectious disease in small ruminants and has been rapidly spreading in many parts of Africa, the Middle East, and Asia. Although vaccination is considered to be an effective means of controlling PPR, the heat-sensitive nature of the vaccines against PPRV greatly limits their application in areas with a hot climate. In the present study, we investigated the anti-PPRV effects of favipiravir and sought to identify the underlying mechanisms in vitro using the Vero cell line. MTT assays, Western blotting, indirect immunofluorescence assays, virus plaque formation assays, and qRT-PCR were used to assess the effects of favipiravir on the life cycle of PPRV and the expression of RNA-dependent RNA polymerase (RdRp). Additionally, the expression levels of JAK1, STAT1, phosphorylated (p)-STAT1, PI3K, AKT, and p-AKT, as well as those of signaling molecules acting downstream of the JAK/STAT and PI3K/AKT signaling pathways, were determined by Western blotting and qRT-PCR. The results indicated that, in PPRV-infected, favipiravir-treated Vero cells, the attachment, invasion, replication, and release of PPRV were significantly inhibited, as was the expression of RdRp, when compared with that in untreated PPRV-infected cells. Furthermore, in favipiravir-treated cells, the expression of JAK1 and STAT1 was downregulated, whereas that of p-STAT1 was significantly upregulated. Similarly, the expression levels of PKR, IRF9, ISG54, and MxA proteins that are associated with innate antiviral activity in host cells were also markedly increased. Moreover, with favipiravir treatment, the expression of PI3K and p-AKT and the p-AKT/AKT ratio were significantly decreased, whereas the expression of AKT was noticeably upregulated. The expression of GSK3, NF-κB p65, p-NF-κB p65, and BAD was also increased with favipiravir treatment, while the expression of CREB, p-CREB, p-GSK3, and Bcl-2 was slightly decreased. In addition, all the p-GSK3/GSK3, p-CREB/CREB, p-NF-κB/NF-κB, and p-BAD/BAD ratios were significantly reduced in favipiravir-treated cells. These results implied that the antiviral effectivity of favipiravir against PPRV is mediated by the JAK/STAT and PI3K/AKT pathways and that favipiravir has potential for use as an effective antiviral agent against PPRV.
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spelling pubmed-84505312021-09-21 Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways Zhang, Weifeng Deng, Hualong Liu, Yanfen Chen, Shaohong Liu, You Zhao, Yuntao Front Vet Sci Veterinary Science Peste des petits ruminants virus (PPRV), belonging to the genus Morbillivirus in the family Paramyxoviridae, causes severe infectious disease in small ruminants and has been rapidly spreading in many parts of Africa, the Middle East, and Asia. Although vaccination is considered to be an effective means of controlling PPR, the heat-sensitive nature of the vaccines against PPRV greatly limits their application in areas with a hot climate. In the present study, we investigated the anti-PPRV effects of favipiravir and sought to identify the underlying mechanisms in vitro using the Vero cell line. MTT assays, Western blotting, indirect immunofluorescence assays, virus plaque formation assays, and qRT-PCR were used to assess the effects of favipiravir on the life cycle of PPRV and the expression of RNA-dependent RNA polymerase (RdRp). Additionally, the expression levels of JAK1, STAT1, phosphorylated (p)-STAT1, PI3K, AKT, and p-AKT, as well as those of signaling molecules acting downstream of the JAK/STAT and PI3K/AKT signaling pathways, were determined by Western blotting and qRT-PCR. The results indicated that, in PPRV-infected, favipiravir-treated Vero cells, the attachment, invasion, replication, and release of PPRV were significantly inhibited, as was the expression of RdRp, when compared with that in untreated PPRV-infected cells. Furthermore, in favipiravir-treated cells, the expression of JAK1 and STAT1 was downregulated, whereas that of p-STAT1 was significantly upregulated. Similarly, the expression levels of PKR, IRF9, ISG54, and MxA proteins that are associated with innate antiviral activity in host cells were also markedly increased. Moreover, with favipiravir treatment, the expression of PI3K and p-AKT and the p-AKT/AKT ratio were significantly decreased, whereas the expression of AKT was noticeably upregulated. The expression of GSK3, NF-κB p65, p-NF-κB p65, and BAD was also increased with favipiravir treatment, while the expression of CREB, p-CREB, p-GSK3, and Bcl-2 was slightly decreased. In addition, all the p-GSK3/GSK3, p-CREB/CREB, p-NF-κB/NF-κB, and p-BAD/BAD ratios were significantly reduced in favipiravir-treated cells. These results implied that the antiviral effectivity of favipiravir against PPRV is mediated by the JAK/STAT and PI3K/AKT pathways and that favipiravir has potential for use as an effective antiviral agent against PPRV. Frontiers Media S.A. 2021-09-06 /pmc/articles/PMC8450531/ /pubmed/34552976 http://dx.doi.org/10.3389/fvets.2021.722840 Text en Copyright © 2021 Zhang, Deng, Liu, Chen, Liu and Zhao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
Zhang, Weifeng
Deng, Hualong
Liu, Yanfen
Chen, Shaohong
Liu, You
Zhao, Yuntao
Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title_full Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title_fullStr Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title_full_unstemmed Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title_short Antiviral Effectivity of Favipiravir Against Peste Des Petits Ruminants Virus Is Mediated by the JAK/STAT and PI3K/AKT Pathways
title_sort antiviral effectivity of favipiravir against peste des petits ruminants virus is mediated by the jak/stat and pi3k/akt pathways
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450531/
https://www.ncbi.nlm.nih.gov/pubmed/34552976
http://dx.doi.org/10.3389/fvets.2021.722840
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