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Abstract

The Epstein-Barr virus efficiently transforms primary B cells. In this thesis I show that this process starts immediately after cellular exposure to viral particles that activate STAT3 and p38/MK2, resulting in the expression of viral transforming genes. Indeed, virus binding to B cells led to activation of intracytoplasmic tyrosine kinases and of STAT3. Tegument proteins within the virion in turn activated the p38-MK2-ZFP36L1 pathway upon cellular entry, independently of the viral DNA. ZFP36L1 is a stress response protein that targets transcripts with an AU-rich 3’UTR and accordingly reduced 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 secretion. However, cytokine release was much stronger in some individuals, which might have clinical consequences. p38 or STAT3 inactivation largely inhibited latent gene transcription without impeding infection itself, showing that proteins present in the virion influence events independent of virus entry. 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 modulating cytokine release.