Abstract
Burkitt’s lymphoma (BL) is the most common childhood cancer in equatorial Africa, and is endemic to areas where people are chronically co-infected with Epstein-Barr virus (EBV) and the malaria pathogen Plasmodium falciparum. The contribution of these pathogens in the oncogenic process remains poorly understood. We showed earlier that the activation of Toll-like receptor (TLR) 9 by hemozoin, a disposal product formed from the digestion of blood by P. falciparum, suppresses the lytic reactivation of EBV in BL cells. EBV lytic reactivation is regulated by the expression of transcription factor Zta (ZEBRA), encoded by the EBV gene BZLF1. Here, we explore in the BL cell line Akata, the mechanism involved in repression by TLR9 of expression of BZLF1. We show that BZLF1 repression is mediated upon TLR9 engagement by a mechanism that is largely independent of de novo protein synthesis. By CRISPR/Cas9-induced inactivation of TLR9, MyD88, IRAK4 and IRAK1 we confirm that BZLF1 repression is dependent on functional TLR9 and MyD88 signaling, and identify IRAK4 as an essential element for TLR9-induced repression of BZLF1 expression upon BCR cross-linking. Our results unprecedentedly show that TLR9-mediated inhibition of lytic EBV is largely independent of new protein synthesis and demonstrate the central roles of MyD88 and IRAK4 in this process contributing to EBV’s persistence in the host’s B-cell pool.
Highlights
Primary infection with Epstein-Barr virus (EBV) is mostly asymptomatic, and more than 90% of the adult population worldwide carries the virus after it has established reversible latent infection [1,2]
We have previously shown that TLR9-triggering by ODN CpG 2006 or Hemozoin inhibits EBV lytic reactivation, i.e. expression of BZLF1, induced by B-cell receptor (BCR) cross-linking in Burkitt’s lymphoma (BL) cells in vitro [26]
We wanted to understand if BZLF1 expression is inhibited directly, e.g. through post-translational modification of existing proteins induced by the TLR9 signaling, or indirectly, through de novo expression of proteins, e.g. of a transcription or repressor factor expressed upon TLR9 stimulation
Summary
Primary infection with Epstein-Barr virus (EBV) is mostly asymptomatic, and more than 90% of the adult population worldwide carries the virus after it has established reversible latent infection [1,2]. TLR9-induced suppression of EBV’s BZLF1 in BL cells analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
