Cargando…

A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response

Flavivirus infection of cells induces massive rearrangements of the endoplasmic reticulum (ER) membrane to form viral replication organelles (ROs) which segregates viral RNA replication intermediates from the cytoplasmic RNA sensors. Among other viral nonstructural (NS) proteins, available evidence...

Descripción completa

Detalles Bibliográficos
Autores principales: Gao, Zhao, Zhang, Xuexiang, Zhang, Lin, Wu, Shuo, Ma, Julia, Wang, Fuxuan, Zhou, Yan, Dai, Xinghong, Bullitt, Esther, Du, Yanming, Guo, Ju-Tao, Chang, Jinhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809586/
https://www.ncbi.nlm.nih.gov/pubmed/35061864
http://dx.doi.org/10.1371/journal.ppat.1010271
_version_ 1784644049580326912
author Gao, Zhao
Zhang, Xuexiang
Zhang, Lin
Wu, Shuo
Ma, Julia
Wang, Fuxuan
Zhou, Yan
Dai, Xinghong
Bullitt, Esther
Du, Yanming
Guo, Ju-Tao
Chang, Jinhong
author_facet Gao, Zhao
Zhang, Xuexiang
Zhang, Lin
Wu, Shuo
Ma, Julia
Wang, Fuxuan
Zhou, Yan
Dai, Xinghong
Bullitt, Esther
Du, Yanming
Guo, Ju-Tao
Chang, Jinhong
author_sort Gao, Zhao
collection PubMed
description Flavivirus infection of cells induces massive rearrangements of the endoplasmic reticulum (ER) membrane to form viral replication organelles (ROs) which segregates viral RNA replication intermediates from the cytoplasmic RNA sensors. Among other viral nonstructural (NS) proteins, available evidence suggests for a prominent role of NS4B, an ER membrane protein with multiple transmembrane domains, in the formation of ROs and the evasion of the innate immune response. We previously reported a benzodiazepine compound, BDAA, which specifically inhibited yellow fever virus (YFV) replication in cultured cells and in vivo in hamsters, with resistant mutation mapped to P219 of NS4B protein. In the following mechanistic studies, we found that BDAA specifically enhances YFV induced inflammatory cytokine response in association with the induction of dramatic structural alteration of ROs and exposure of double-stranded RNA (dsRNA) in virus-infected cells. Interestingly, the BDAA-enhanced cytokine response in YFV-infected cells is attenuated in RIG-I or MAD5 knockout cells and completely abolished in MAVS knockout cells. However, BDAA inhibited YFV replication at a similar extent in the parent cells and cells deficient of RIG-I, MDA5 or MAVS. These results thus provided multiple lines of biological evidence to support a model that BDAA interaction with NS4B may impair the integrity of YFV ROs, which not only inhibits viral RNA replication, but also promotes the release of viral RNA from ROs, which consequentially activates RIG-I and MDA5. Although the innate immune enhancement activity of BDAA is not required for its antiviral activity in cultured cells, its dual antiviral mechanism is unique among all the reported antiviral agents thus far and warrants further investigation in animal models in future.
format Online
Article
Text
id pubmed-8809586
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-88095862022-02-03 A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response Gao, Zhao Zhang, Xuexiang Zhang, Lin Wu, Shuo Ma, Julia Wang, Fuxuan Zhou, Yan Dai, Xinghong Bullitt, Esther Du, Yanming Guo, Ju-Tao Chang, Jinhong PLoS Pathog Research Article Flavivirus infection of cells induces massive rearrangements of the endoplasmic reticulum (ER) membrane to form viral replication organelles (ROs) which segregates viral RNA replication intermediates from the cytoplasmic RNA sensors. Among other viral nonstructural (NS) proteins, available evidence suggests for a prominent role of NS4B, an ER membrane protein with multiple transmembrane domains, in the formation of ROs and the evasion of the innate immune response. We previously reported a benzodiazepine compound, BDAA, which specifically inhibited yellow fever virus (YFV) replication in cultured cells and in vivo in hamsters, with resistant mutation mapped to P219 of NS4B protein. In the following mechanistic studies, we found that BDAA specifically enhances YFV induced inflammatory cytokine response in association with the induction of dramatic structural alteration of ROs and exposure of double-stranded RNA (dsRNA) in virus-infected cells. Interestingly, the BDAA-enhanced cytokine response in YFV-infected cells is attenuated in RIG-I or MAD5 knockout cells and completely abolished in MAVS knockout cells. However, BDAA inhibited YFV replication at a similar extent in the parent cells and cells deficient of RIG-I, MDA5 or MAVS. These results thus provided multiple lines of biological evidence to support a model that BDAA interaction with NS4B may impair the integrity of YFV ROs, which not only inhibits viral RNA replication, but also promotes the release of viral RNA from ROs, which consequentially activates RIG-I and MDA5. Although the innate immune enhancement activity of BDAA is not required for its antiviral activity in cultured cells, its dual antiviral mechanism is unique among all the reported antiviral agents thus far and warrants further investigation in animal models in future. Public Library of Science 2022-01-21 /pmc/articles/PMC8809586/ /pubmed/35061864 http://dx.doi.org/10.1371/journal.ppat.1010271 Text en © 2022 Gao 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
Gao, Zhao
Zhang, Xuexiang
Zhang, Lin
Wu, Shuo
Ma, Julia
Wang, Fuxuan
Zhou, Yan
Dai, Xinghong
Bullitt, Esther
Du, Yanming
Guo, Ju-Tao
Chang, Jinhong
A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title_full A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title_fullStr A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title_full_unstemmed A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title_short A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response
title_sort yellow fever virus ns4b inhibitor not only suppresses viral replication, but also enhances the virus activation of rig-i-like receptor-mediated innate immune response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809586/
https://www.ncbi.nlm.nih.gov/pubmed/35061864
http://dx.doi.org/10.1371/journal.ppat.1010271
work_keys_str_mv AT gaozhao ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhangxuexiang ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhanglin ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT wushuo ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT majulia ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT wangfuxuan ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhouyan ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT daixinghong ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT bullittesther ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT duyanming ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT guojutao ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT changjinhong ayellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT gaozhao yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhangxuexiang yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhanglin yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT wushuo yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT majulia yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT wangfuxuan yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT zhouyan yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT daixinghong yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT bullittesther yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT duyanming yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT guojutao yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse
AT changjinhong yellowfevervirusns4binhibitornotonlysuppressesviralreplicationbutalsoenhancesthevirusactivationofrigilikereceptormediatedinnateimmuneresponse