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TLR9 triggering in Burkitt's lymphoma cell lines suppresses the EBV BZLF1 transcription via histone modification

Oncogene volume 29, pages 4588–4598 (2010)Cite this article

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Abstract

Endemic Burkitt's lymphoma (BL) is considered to preferentially develop in equatorial Africa because of chronic co-infection with Epstein–Barr virus (EBV) and the malaria pathogen Plasmodium falciparum. The interaction and contribution of both pathogens in the oncogenic process are poorly understood. Earlier, we showed that immune activation with a synthetic Toll-like receptor 9 (TLR9) ligand suppresses the initiation of EBV lytic replication in primary human B cells. In this study we investigate the mechanism involved in the suppression of EBV lytic gene expression in BL cell lines. We show that this suppression is dependent on functional TLR9 and MyD88 signaling but independent of downstream signaling elements, including phosphatidylinositol-3 kinase, mitogen-activated protein kinases and nuclear factor-κB. We identified TLR9 triggering resulting in histone modifications to negatively affect the activation of the promoter of EBV's master regulatory lytic gene BZLF1. Finally, we show that P. falciparum hemozoin, a natural TLR9 ligand, suppresses induction of EBV lytic gene expression in a dose-dependent manner. Thus, we provide evidence for a possible interaction between P. falciparum and EBV at the B-cell level and the mechanism involved in suppressing lytic and thereby reinforcing latent EBV that has unique oncogenic potential.

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Acknowledgements

We thank Jürg Tschopp, Hans-Peter Beck and Sebastian Rusch for providing reagents. This work was supported by grants from the Cancer League of the Canton Zurich, the Swiss National Foundation (no. 310040-114118), Oncosuisse, the Forschungskredit of the University of Zurich (no. 54192002) and UBS donation by a client.

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Author notes

  1. G T Melroe

    Present address: 4Current address: Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.,

  2. M P Rechsteiner

    Present address: 5Current address: Institute of Pathology, University Hospital of Zurich, Zurich, Switzerland.,

  3. M Dorner

    Present address: 6Current address: Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY, USA.,

Authors and Affiliations

  1. Division of Infectious Diseases and Hospital Epidemiology, Laboratory for Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland

    L Zauner, G T Melroe, J A Sigrist, M P Rechsteiner, M Dorner, M Arnold, C Berger, M Bernasconi & D Nadal

  2. Division of Oncology, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland

    B W Schaefer

  3. Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

    R F Speck

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  1. L Zauner
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Correspondence to D Nadal.

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Zauner, L., Melroe, G., Sigrist, J. et al. TLR9 triggering in Burkitt's lymphoma cell lines suppresses the EBV BZLF1 transcription via histone modification. Oncogene 29, 4588–4598 (2010). https://doi.org/10.1038/onc.2010.203

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