TLR9 triggering in Burkitt's lymphoma cell lines suppresses the EBV BZLF1 transcription via histone modification.
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-kappaB. 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.
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
L
Zauner
G T
GT
Melroe
J A
JA
Sigrist
M P
MP
Rechsteiner
M
M
Dorner
M
M
Arnold
C
C
Berger
M
M
Bernasconi
B W
BW
Schaefer
R F
RF
Speck
D
D
Nadal
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000473:pathology* / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D006420:Hemeproteins / Q000378:metabolism / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010963:Plasmodium falciparum / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015800:Protozoan Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects
C063676:BZLF1 protein, Herpesvirus 4, Human; D006420:Hemeproteins; D006657:Histones; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D015800:Protozoan Proteins; D051217:Toll-Like Receptor 9; D015534:Trans-Activators; C020753:hemozoin