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@ARTICLE{Baccianti:284771,
      author       = {F. Baccianti$^*$ and C. Masson$^*$ and S. Delecluse$^*$ and
                      Z. Li$^*$ and R. Poirey$^*$ and H.-J. Delecluse$^*$},
      title        = {{E}pstein-{B}arr virus infectious particles initiate {B}
                      cell transformation and modulate cytokine response.},
      journal      = {mBio},
      volume       = {14},
      number       = {5},
      issn         = {2161-2129},
      address      = {Washington, DC},
      publisher    = {American Society for Microbiology},
      reportid     = {DKFZ-2023-02082},
      pages        = {e0178423},
      year         = {2023},
      note         = {#EA:F100#LA:F100# / 2023 Oct 13;14(5):e0178423},
      abstract     = {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.},
      keywords     = {Epstein-Barr virus (Other) / STAT3 (Other) / ZFP36L1
                      (Other) / p38-MK2 (Other)},
      cin          = {F100},
      ddc          = {570},
      cid          = {I:(DE-He78)F100-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37830871},
      doi          = {10.1128/mbio.01784-23},
      url          = {https://inrepo02.dkfz.de/record/284771},
}