Epstein-Barr Virus BZLF1-Mediated Down-regulation of Pro-inflammatory Factors is Essential for Optimal Lytic Viral Replication.
Fiche publication
Date publication
novembre 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DELECLUSE Henri-Jacques
Tous les auteurs :
Li Y, Long X, Huang L, Yang M, Yuan Y, Wang Y, Delecluse HJ, Kuang E
Lien Pubmed
Résumé
Elevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, the inflammatory response and its biological significance during the lytic EBV cycle remain elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the pro-inflammatory factor TNFalpha by binding to the promoter of TNFalpha and preventing NFkappaB activation. A BZLF1Delta207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the pro-inflammatory factors TNFalpha and IFNgamma and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNFalpha depletion restored the viral replication mediated by BZLF1Delta207-210. Furthermore, a combination of TNFalpha- and IFNgamma-neutralizing antibodies recovered BZLF1Delta207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNFalpha and IFNgamma secretion during the lytic cycle. These results suggest that the EBV BZLF1 attenuates the pro-inflammatory responses to facilitate viral replication. IMPORTANCE: The pro-inflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as transcriptional suppressor of the inflammatory factors TNFalpha and IFNgamma and confirm that BZLF1-facilitated escape from the TNFalpha and IFNgamma response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response.
Référence
J Virol. 2015 Nov 4. pii: JVI.01921-15.