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

Zauner, Ludwig; Melroe, Gregory T.; Sigrist, Jürg A.; Rechsteiner, Markus; Dorner, Marcus; Arnold, Markus; Berger, Christoph; Bernasconi, Michele; Schaefer, Beat; Speck, Roberto F.; Nadal, David

doi:10.1038/onc.2010.203

Cited by 25 publications

(43 citation statements)

References 43 publications

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“…2A). It seems likely that this feature is shared by other gammaherpesviruses, as previous studies in our laboratory demonstrated that stimulation of TLR9 similarly leads to a suppression of EBV's master regulator lytic BZLF1 gene in Burkitt's lymphoma cells (8,9). Our finding that signaling via TLR7 suppresses MHV 68 reactivation is unprecedented.…”

Section: Discussionsupporting

confidence: 55%

“…Indeed, with respect to EBV-associated B-cell malignancies, P. falciparum malaria is epidemiologically associated with endemic BL, and the parasite was reported to directly stimulate TLR9 (11,12). Earlier we showed that P. falciparum hemozoin suppresses lytic reactivation of EBV in BL cells (9), further underscoring activation of TLR signaling pathways as a possible mechanistic link between chronic malaria infection and the incidence of endemic BL. The situation in KSHV-associated primary effusion lymphoma, however, may be distinct, as suggested by the lytic reactivation of KSHV following triggering of TLR7/8 (7).…”

Section: Discussionmentioning

confidence: 95%

“…Intrinsic and extrinsic factors are thought to control lytic reactivation of gammaherpesviruses. Activation of the innate immune system, in particular, signaling via Toll-like receptors (TLRs), has been shown to be an important factor in the balance between latency and lytic reactivation (6)(7)(8)(9). TLRs are a family of pattern-recognition receptors that play a central role in innate immunity (10).…”

mentioning

confidence: 99%

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Activation of NF-κB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation

Florian

Yamauchi

Murat

et al. 2014

J Virol

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In order to understand and possibly treat B-cell malignancies associated with latent gammaherpesvirus infection, it is vital to understand the factors that control the balance between the two transcriptional states of gammaherpesviruses: latency and lytic replication. We used murine gammaherpesvirus 68 (MHV 68) as a model system to investigate how engagement of endosomal Toll-like receptors (TLRs) impacts reactivation from latency in vitro and establishment of latent infection in vivo. We found that treatment with TLR7 ligand R848 or TLR9 ligand CpG oligodeoxynucleotide (ODN) suppresses reactivation of MHV 68 in vitro. These suppressive effects correlated with the ability to activate cellular transcription factor NF-B. Downregulation of TLR9 by RNA interference in vitro led to a reduction of nuclear levels of NF-B p65 and consequently to an increase of spontaneous reactivation in cells latently infected with MHV 68, indicating that the TLR9 pathway suppresses spontaneous reactivation events. In vivo, sustained stimulation of TLR7 by repeated R848 treatment led to an increased frequency of infected splenocytes compared to mock-treated control results. Frequencies of infected splenic B cells in tlr7 ؊/؊ or tlr9 ؊/؊ mice after establishment of latency did not differ from those seen with their wild-type counterparts. Nevertheless, MHV 68-infected B cells from tlr9 ؊/؊ mice showed a higher frequency of reactivation than B cells from wild-type or tlr7 ؊/؊ mice in ex vivo reactivation assays. Thus, we show a suppressive effect of TLR7 or TLR9 triggering on MHV 68 reactivation that correlates with NF-B activation and that the mere presence of a functional TLR9 signaling pathway contributes to dampen lytic gammaherpesvirus reactivation in infected cells. IMPORTANCEA hallmark of gammaherpesviruses is their establishment of latency in B cells that is reversible through lytic reactivation. Latency can result in B-cell malignancies. Activation of the innate immune system is thought to contribute to controlling the switch between the transcriptional states of latency and reactivation. Nevertheless, the mechanisms involved are not clear. Here, we show that engagement of Toll-like receptor 7 (TLR7) and TLR9 suppresses reactivation of murine gammaherpesvirus MHV 68 in vitro and that stimulation of TLR7 in vivo increases the frequency of infected cells. TLR7 and TLR9 are innate immunity sensors of nucleic acids localized in endosomes. Additionally, we demonstrate that impairment of TLR9 signaling in latently infected B cells leads to increased reactivation. Thus, activated endosomal TLR7 and TLR9 pathways play an important role in promoting establishment of latent gammaherpesvirus infection. Counteracting signaling of these pathways allows reactivation and could represent treatment targets in gammaherpesvirus-associated malignancies.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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Activation of NF-κB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation

Florian

Yamauchi

Murat

et al. 2014

J Virol

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“…In the case of endemic Burkitt's lymphoma, TLR9 may play a role in the survival of the malignant B cells by preventing the lytic phase of the Epstein-Barr virus [82]. Activation of TLR9 causes decreased levels of phosphorylated histone H3 and acetylated histones H4 and H3 bound to the Epstein-Barr virus master regulatory lytic gene promoter, thus preventing the virus from entering the lytic phase [82].…”

Section: Toll-like Receptors and The Governing Epigenetic Mechanisms:mentioning

confidence: 99%

Epigenetic Regulation of Toll-Like Receptor Signaling: Implications for Cancer Development

Boi¹,

Elsawa²

2013

Med Epigenet

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The innate immune response acts in a myriad of ways to protect the host from pathogenic agents. This interplay requires changes in gene expression patterns that allow the host to effectively respond. Epigenetic mechanisms are important in this scenario. Understanding these mechanisms is of great interest for the development of appropriate therapies modulating the immune response. One of the important receptor families responsible for the activity of the innate immune system is the Toll-like receptor (TLR) family. This family is important for the innate immune response to infections and has been implicated to play a role in cancer. Understanding the epigenetic mechanisms regulated by TLR signaling is important for the development of novel therapies for a multitude of diseases including cancer. In this article, we present an overview of this pathway and its role in carcinogenesis, and we discuss the epigenetic mechanisms regulating its activity.

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“…TLRs 3,7,8, and 9 were demonstrated to recognize different forms of microbial-derived nucleic acid. TLR9 detects unmethylated CpG motifs found in the genomic DNA from a variety of viruses, such as EBV, human papillomavirus type 16 (HPV16), and HSV-2 (1)(2)(3)(4)(5). Although TLR9 signaling in hematopoietic cells was demonstrated to control infection of several DNA viruses, TLR9 is also expressed on epithelial cells, such as keratinocytes (6)(7)(8).…”

mentioning

confidence: 99%

TLR9 Transcriptional Regulation in Response to Double-Stranded DNA Viruses

Zannetti

Parroche

Panaye

et al. 2014

The Journal of Immunology

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The stimulation of TLRs by pathogen-derived molecules leads to the production of proinflammatory cytokines. Because uncontrolled inflammation can be life threatening, TLR regulation is important; however, few studies have identified the signaling pathways that contribute to the modulation of TLR expression. In this study, we examined the relationship between activation and the transcriptional regulation of TLR9. We demonstrate that infection of primary human epithelial cells, B cells, and plasmacytoid dendritic cells with dsDNA viruses induces a regulatory temporary negative-feedback loop that blocks TLR9 transcription and function. TLR9 transcriptional downregulation was dependent on TLR9 signaling and was not induced by TLR5 or other NF-κB activators, such as TNF-α. Engagement of the TLR9 receptor induced the recruitment of a suppressive complex, consisting of NF-κBp65 and HDAC3, to an NF-κB cis element on the TLR9 promoter. Knockdown of HDAC3 blocked the transient suppression in which TLR9 function was restored. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR9, immune induction, and inflammation against viruses.

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

Cited by 25 publications

References 43 publications

Activation of NF-κB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation

Activation of NF-κB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation

Epigenetic Regulation of Toll-Like Receptor Signaling: Implications for Cancer Development

TLR9 Transcriptional Regulation in Response to Double-Stranded DNA Viruses

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