Cargando…
Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response
The Epstein-Barr virus (EBV) efficiently transforms primary B cells. Here, we show that this process starts immediately after cellular exposure to infectious viral particles. Virus binding to B cells led to the activation of intracytoplasmic tyrosine kinases and STAT3. Tegument proteins within the v...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653912/ https://www.ncbi.nlm.nih.gov/pubmed/37830871 http://dx.doi.org/10.1128/mbio.01784-23 |
_version_ | 1785136515954769920 |
---|---|
author | Baccianti, Francesco Masson, Charlène Delecluse, Susanne Li, Zhe Poirey, Remy Delecluse, Henri-Jacques |
author_facet | Baccianti, Francesco Masson, Charlène Delecluse, Susanne Li, Zhe Poirey, Remy Delecluse, Henri-Jacques |
author_sort | Baccianti, Francesco |
collection | PubMed |
description | The Epstein-Barr virus (EBV) efficiently transforms primary B cells. Here, we show that this process starts immediately after cellular exposure to infectious viral particles. Virus binding to B cells led to the activation of intracytoplasmic tyrosine kinases and STAT3. Tegument proteins within the virion in turn activated the p38-MK2 pathway upon cell entry, independently of the viral DNA. Engagement of STAT3 and p38/MK2, two pro-inflammatory pathways, was essential for expression of the key EBV transforming gene EBNA2 but also facilitated IL-6 and TNFα release. However, these pathways simultaneously activated ZFP36L1, a stress response protein that targets transcripts with an AU-rich 3′UTR, to reduce IL-6 and TNFα transcription in infected cells. Expression of viral latent proteins after infection amplified the viral effects on p38 and MK2, but also on ZFP36L1, altogether resulting in a transitory and limited increase in IL-6 and TNFα transcription and release. Thus, EBV virions are not merely vehicles that allow injection of the viral DNA into the nucleus but manipulate cellular pathways to initiate transformation while limiting cytokine release. IMPORTANCE: The Epstein-Barr virus efficiently infects and transforms B lymphocytes. During this process, infectious viral particles transport the viral genome to the nucleus of target cells. We show here that these complex viral structures serve additional crucial roles by activating transcription of the transforming genes encoded by the virus. We show that components of the infectious particle sequentially activate proinflammatory B lymphocyte signaling pathways that, in turn, activate viral gene expression but also cause cytokine release. However, virus infection activates expression of ZFP36L1, an RNA-binding stress protein that limits the length and the intensity of the cytokine response. Thus, the infectious particles can activate viral gene expression and initiate cellular transformation at the price of a limited immune response. |
format | Online Article Text |
id | pubmed-10653912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-106539122023-10-13 Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response Baccianti, Francesco Masson, Charlène Delecluse, Susanne Li, Zhe Poirey, Remy Delecluse, Henri-Jacques mBio Research Article The Epstein-Barr virus (EBV) efficiently transforms primary B cells. Here, we show that this process starts immediately after cellular exposure to infectious viral particles. Virus binding to B cells led to the activation of intracytoplasmic tyrosine kinases and STAT3. Tegument proteins within the virion in turn activated the p38-MK2 pathway upon cell entry, independently of the viral DNA. Engagement of STAT3 and p38/MK2, two pro-inflammatory pathways, was essential for expression of the key EBV transforming gene EBNA2 but also facilitated IL-6 and TNFα release. However, these pathways simultaneously activated ZFP36L1, a stress response protein that targets transcripts with an AU-rich 3′UTR, to reduce IL-6 and TNFα transcription in infected cells. Expression of viral latent proteins after infection amplified the viral effects on p38 and MK2, but also on ZFP36L1, altogether resulting in a transitory and limited increase in IL-6 and TNFα transcription and release. Thus, EBV virions are not merely vehicles that allow injection of the viral DNA into the nucleus but manipulate cellular pathways to initiate transformation while limiting cytokine release. IMPORTANCE: The Epstein-Barr virus efficiently infects and transforms B lymphocytes. During this process, infectious viral particles transport the viral genome to the nucleus of target cells. We show here that these complex viral structures serve additional crucial roles by activating transcription of the transforming genes encoded by the virus. We show that components of the infectious particle sequentially activate proinflammatory B lymphocyte signaling pathways that, in turn, activate viral gene expression but also cause cytokine release. However, virus infection activates expression of ZFP36L1, an RNA-binding stress protein that limits the length and the intensity of the cytokine response. Thus, the infectious particles can activate viral gene expression and initiate cellular transformation at the price of a limited immune response. American Society for Microbiology 2023-10-13 /pmc/articles/PMC10653912/ /pubmed/37830871 http://dx.doi.org/10.1128/mbio.01784-23 Text en Copyright © 2023 Baccianti 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 | Research Article Baccianti, Francesco Masson, Charlène Delecluse, Susanne Li, Zhe Poirey, Remy Delecluse, Henri-Jacques Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title | Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title_full | Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title_fullStr | Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title_full_unstemmed | Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title_short | Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response |
title_sort | epstein-barr virus infectious particles initiate b cell transformation and modulate cytokine response |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653912/ https://www.ncbi.nlm.nih.gov/pubmed/37830871 http://dx.doi.org/10.1128/mbio.01784-23 |
work_keys_str_mv | AT bacciantifrancesco epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse AT massoncharlene epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse AT deleclusesusanne epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse AT lizhe epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse AT poireyremy epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse AT deleclusehenrijacques epsteinbarrvirusinfectiousparticlesinitiatebcelltransformationandmodulatecytokineresponse |