Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies
Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete c...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682993/ https://www.ncbi.nlm.nih.gov/pubmed/36317881 http://dx.doi.org/10.1128/jvi.01309-22 |
_version_ | 1784834977968422912 |
---|---|
author | Li, Jiao Xue, Ling Wang, Jiachao Meng, Aihong Qiao, Jiajun Li, Miao Wang, Xiuli Meng, Lingtong Ning, Jingyuan Gao, Xue Li, Wenjian Ma, Cuiqing Wei, Lin |
author_facet | Li, Jiao Xue, Ling Wang, Jiachao Meng, Aihong Qiao, Jiajun Li, Miao Wang, Xiuli Meng, Lingtong Ning, Jingyuan Gao, Xue Li, Wenjian Ma, Cuiqing Wei, Lin |
author_sort | Li, Jiao |
collection | PubMed |
description | Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in nonimmune cells is rarely clear. In this study, we detected that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo or in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction, or viral adhesion or entry inhibition. In contrast, it was related to the preferential recruitment and activation of the adaptor Gαi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation; explicitly, phosphorylated STAT3 (p-STAT3) was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of nonimmune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction. IMPORTANCE Our results revealed a novel mechanism by which RSV escapes innate immunity. That is, although it induces high CCL5 expression, RSV might attenuate the binding of CCL5 by downregulating the expression of CCR1 in respiratory epithelial cells to weaken the inhibitory effect of CCR1 on HSP90 activity and thereby facilitate RSV replication in nonimmune cells. This study provides a new target for the development of co-antiviral inhibitors against other components of the host and co-molecular chaperone/HSP90 and provides a scientific basis for the search for effective broad-spectrum antiviral drugs. |
format | Online Article Text |
id | pubmed-9682993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96829932022-11-24 Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies Li, Jiao Xue, Ling Wang, Jiachao Meng, Aihong Qiao, Jiajun Li, Miao Wang, Xiuli Meng, Lingtong Ning, Jingyuan Gao, Xue Li, Wenjian Ma, Cuiqing Wei, Lin J Virol Virus-Cell Interactions Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in nonimmune cells is rarely clear. In this study, we detected that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo or in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction, or viral adhesion or entry inhibition. In contrast, it was related to the preferential recruitment and activation of the adaptor Gαi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation; explicitly, phosphorylated STAT3 (p-STAT3) was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of nonimmune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction. IMPORTANCE Our results revealed a novel mechanism by which RSV escapes innate immunity. That is, although it induces high CCL5 expression, RSV might attenuate the binding of CCL5 by downregulating the expression of CCR1 in respiratory epithelial cells to weaken the inhibitory effect of CCR1 on HSP90 activity and thereby facilitate RSV replication in nonimmune cells. This study provides a new target for the development of co-antiviral inhibitors against other components of the host and co-molecular chaperone/HSP90 and provides a scientific basis for the search for effective broad-spectrum antiviral drugs. American Society for Microbiology 2022-11-01 /pmc/articles/PMC9682993/ /pubmed/36317881 http://dx.doi.org/10.1128/jvi.01309-22 Text en Copyright © 2022 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 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Virus-Cell Interactions Li, Jiao Xue, Ling Wang, Jiachao Meng, Aihong Qiao, Jiajun Li, Miao Wang, Xiuli Meng, Lingtong Ning, Jingyuan Gao, Xue Li, Wenjian Ma, Cuiqing Wei, Lin Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title | Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title_full | Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title_fullStr | Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title_full_unstemmed | Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title_short | Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies |
title_sort | activation of the chemokine receptor ccr1 and preferential recruitment of gαi suppress rsv replication: implications for developing novel respiratory syncytial virus treatment strategies |
topic | Virus-Cell Interactions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9682993/ https://www.ncbi.nlm.nih.gov/pubmed/36317881 http://dx.doi.org/10.1128/jvi.01309-22 |
work_keys_str_mv | AT lijiao activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT xueling activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT wangjiachao activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT mengaihong activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT qiaojiajun activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT limiao activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT wangxiuli activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT menglingtong activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT ningjingyuan activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT gaoxue activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT liwenjian activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT macuiqing activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies AT weilin activationofthechemokinereceptorccr1andpreferentialrecruitmentofgaisuppressrsvreplicationimplicationsfordevelopingnovelrespiratorysyncytialvirustreatmentstrategies |