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pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including...

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Autores principales: Li, Jiangnan, Song, Jie, Kang, Li, Huang, Li, Zhou, Shijun, Hu, Liang, Zheng, Jun, Li, Changyao, Zhang, Xianfeng, He, Xijun, Zhao, Dongming, Bu, Zhigao, Weng, Changjiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341718/
https://www.ncbi.nlm.nih.gov/pubmed/34310655
http://dx.doi.org/10.1371/journal.ppat.1009733
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author Li, Jiangnan
Song, Jie
Kang, Li
Huang, Li
Zhou, Shijun
Hu, Liang
Zheng, Jun
Li, Changyao
Zhang, Xianfeng
He, Xijun
Zhao, Dongming
Bu, Zhigao
Weng, Changjiang
author_facet Li, Jiangnan
Song, Jie
Kang, Li
Huang, Li
Zhou, Shijun
Hu, Liang
Zheng, Jun
Li, Changyao
Zhang, Xianfeng
He, Xijun
Zhao, Dongming
Bu, Zhigao
Weng, Changjiang
author_sort Li, Jiangnan
collection PubMed
description Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.
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spelling pubmed-83417182021-08-06 pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production Li, Jiangnan Song, Jie Kang, Li Huang, Li Zhou, Shijun Hu, Liang Zheng, Jun Li, Changyao Zhang, Xianfeng He, Xijun Zhao, Dongming Bu, Zhigao Weng, Changjiang PLoS Pathog Research Article Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF. Public Library of Science 2021-07-26 /pmc/articles/PMC8341718/ /pubmed/34310655 http://dx.doi.org/10.1371/journal.ppat.1009733 Text en © 2021 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Jiangnan
Song, Jie
Kang, Li
Huang, Li
Zhou, Shijun
Hu, Liang
Zheng, Jun
Li, Changyao
Zhang, Xianfeng
He, Xijun
Zhao, Dongming
Bu, Zhigao
Weng, Changjiang
pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title_full pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title_fullStr pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title_full_unstemmed pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title_short pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production
title_sort pmgf505-7r determines pathogenicity of african swine fever virus infection by inhibiting il-1β and type i ifn production
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341718/
https://www.ncbi.nlm.nih.gov/pubmed/34310655
http://dx.doi.org/10.1371/journal.ppat.1009733
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