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EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection

The establishment of Japanese encephalitis virus (JEV) infection in brain microvascular endothelial cells (BMECs) is thought to be a critical step to induce viral encephalitis with compromised blood–brain barrier (BBB), and the mechanisms involved in this process are not completely understood. In th...

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Autores principales: Zhang, Ya-Ge, Chen, Hao-Wei, Zhang, Hong-Xin, Wang, Ke, Su, Jie, Chen, Yan-Ru, Wang, Xiang-Ru, Fu, Zhen-Fang, Cui, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279666/
https://www.ncbi.nlm.nih.gov/pubmed/35847084
http://dx.doi.org/10.3389/fmicb.2022.894356
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author Zhang, Ya-Ge
Chen, Hao-Wei
Zhang, Hong-Xin
Wang, Ke
Su, Jie
Chen, Yan-Ru
Wang, Xiang-Ru
Fu, Zhen-Fang
Cui, Min
author_facet Zhang, Ya-Ge
Chen, Hao-Wei
Zhang, Hong-Xin
Wang, Ke
Su, Jie
Chen, Yan-Ru
Wang, Xiang-Ru
Fu, Zhen-Fang
Cui, Min
author_sort Zhang, Ya-Ge
collection PubMed
description The establishment of Japanese encephalitis virus (JEV) infection in brain microvascular endothelial cells (BMECs) is thought to be a critical step to induce viral encephalitis with compromised blood–brain barrier (BBB), and the mechanisms involved in this process are not completely understood. In this study, we found that epidermal growth factor receptor (EGFR) is related to JEV escape from interferon-related host innate immunity based on a STRING analysis of JEV-infected primary human brain microvascular endothelial cells (hBMECs) and mouse brain. At the early phase of the infection processes, JEV induced the phosphorylation of EGFR. In JEV-infected hBMECs, a rapid internalization of EGFR that co-localizes with the endosomal marker EEA1 occurred. Using specific inhibitors to block EGFR, reduced production of viral particles was observed. Similar results were also found in an EGFR-KO hBMEC cell line. Even though the process of viral infection in attachment and entry was not noticeably influenced, the induction of IFNs in EGFR-KO hBMECs was significantly increased, which may account for the decreased viral production. Further investigation demonstrated that EGFR downstream cascade ERK, but not STAT3, was involved in the antiviral effect of IFNs, and a lowered viral yield was observed by utilizing the specific inhibitor of ERK. Taken together, the results revealed that JEV induces EGFR activation, leading to a suppression of interferon signaling and promotion of viral replication, which could provide a potential target for future therapies for the JEV infection.
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spelling pubmed-92796662022-07-15 EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection Zhang, Ya-Ge Chen, Hao-Wei Zhang, Hong-Xin Wang, Ke Su, Jie Chen, Yan-Ru Wang, Xiang-Ru Fu, Zhen-Fang Cui, Min Front Microbiol Microbiology The establishment of Japanese encephalitis virus (JEV) infection in brain microvascular endothelial cells (BMECs) is thought to be a critical step to induce viral encephalitis with compromised blood–brain barrier (BBB), and the mechanisms involved in this process are not completely understood. In this study, we found that epidermal growth factor receptor (EGFR) is related to JEV escape from interferon-related host innate immunity based on a STRING analysis of JEV-infected primary human brain microvascular endothelial cells (hBMECs) and mouse brain. At the early phase of the infection processes, JEV induced the phosphorylation of EGFR. In JEV-infected hBMECs, a rapid internalization of EGFR that co-localizes with the endosomal marker EEA1 occurred. Using specific inhibitors to block EGFR, reduced production of viral particles was observed. Similar results were also found in an EGFR-KO hBMEC cell line. Even though the process of viral infection in attachment and entry was not noticeably influenced, the induction of IFNs in EGFR-KO hBMECs was significantly increased, which may account for the decreased viral production. Further investigation demonstrated that EGFR downstream cascade ERK, but not STAT3, was involved in the antiviral effect of IFNs, and a lowered viral yield was observed by utilizing the specific inhibitor of ERK. Taken together, the results revealed that JEV induces EGFR activation, leading to a suppression of interferon signaling and promotion of viral replication, which could provide a potential target for future therapies for the JEV infection. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9279666/ /pubmed/35847084 http://dx.doi.org/10.3389/fmicb.2022.894356 Text en Copyright © 2022 Zhang, Chen, Zhang, Wang, Su, Chen, Wang, Fu and Cui. 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 Microbiology
Zhang, Ya-Ge
Chen, Hao-Wei
Zhang, Hong-Xin
Wang, Ke
Su, Jie
Chen, Yan-Ru
Wang, Xiang-Ru
Fu, Zhen-Fang
Cui, Min
EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title_full EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title_fullStr EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title_full_unstemmed EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title_short EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection
title_sort egfr activation impairs antiviral activity of interferon signaling in brain microvascular endothelial cells during japanese encephalitis virus infection
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279666/
https://www.ncbi.nlm.nih.gov/pubmed/35847084
http://dx.doi.org/10.3389/fmicb.2022.894356
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