EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

Fathallah, Ikbal; Parroche, Peggy; Gruffat, Henri; Zannetti, Claudia; Johansson, Hanna; Yue, Jiping; Manet, Évelyne; Tommasino, Massimo; Sylla, Bakary S.; Hasan, Uzma

doi:10.4049/jimmunol.0903459

Cited by 92 publications

(92 citation statements)

References 38 publications

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“…Note added in proof. Since resubmission of our manuscript, Fathallah et al (55) reported that EBV LMP1, expressed during latency III, can downregulate TLR9 through NF-kB-dependent inhibition of TLR9 transcription.…”

Section: Discussionmentioning

confidence: 91%

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Gent

Griffin

Berkhoff

et al. 2011

The Journal of Immunology

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Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV− and EBV+ human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.

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Section: Discussionmentioning

confidence: 91%

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Gent

Griffin

Berkhoff

et al. 2011

The Journal of Immunology

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“…The C-terminally truncated form of MCPyV LT was generated by modifying the codon 534 AAG to TAA by site-directed mutagenesis and cloned into pcDNA3 or pLXSN. The pcDNA3-LMP-1, pGL3-TLR9 delta NF-B response element (RE), and pcDNA-6-57 KT constructs have been previously described (3,24). The TLR9 promoter luciferase constructs, full length (Ϫ3227/Ϫ1) or deleted (Ϫ1017/Ϫ1, Ϫ640/Ϫ1, Ϫ290/Ϫ1, Ϫ240/Ϫ1, Ϫ160/Ϫ1, Ϫ130/Ϫ1, Ϫ1017a/Ϫ1, and Ϫ1017b/Ϫ1), were a kind gift from Fumihiko Takeshita (Yokohama City University Graduate School of Medicine, Kanagawa, Japan) (31).…”

Section: Expression Vectorsmentioning

confidence: 99%

“…Upon ligand binding, TLR9 induces the transcription factor NF-B in cells of the immune system, leading to increased production of inflammatory mediators (23). Some dsDNA oncogenic viruses, such as Epstein-Barr virus (EBV), hepatitis B virus (HBV), and the mucosal high-risk human papillomavirus 16 (HPV16), inhibit the expression of TLR9 (24)(25)(26)(27)(28).…”

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confidence: 99%

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

Sattar

Shuda

Gheit

et al. 2013

J Virol

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“…In the lytic phase of infection, a number of viral factors help the virus evade the immune response. Different EBV immunoevasins interfere with different steps of the MHC class I antigen presentation pathway (17), mimic immunosuppressive cytokines such as IL-10 (18), or down-regulate Toll-like receptors (TLRs) to avoid production of proinflammatory cytokines (19,20).…”

mentioning

confidence: 99%

RNAs in Epstein–Barr virions control early steps of infection

Jochum

Ruiss

Moosmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Herpesviruses are dsDNA viruses, but their virions may additionally contain RNAs that can be transduced to recipient cells. The biological functions of herpes virion RNA species are unknown. Here we address this issue for EBV, a widespread human herpesvirus with oncogenic potential. We show that EBV-derived particles that include virions, virus-like particles, and subviral vesicles contain viral mRNAs, microRNAs, and other noncoding RNAs. Viral RNAs were transduced during infection and deployed immediate functions that enhanced EBV’s capacity to transform primary B cells. Among these transduced viral RNAs, BZLF1 transcripts transactivated viral promoters triggering the prelatent phase of EBV infection, noncoding EBV-encoded RNA transcripts induced cellular cytokine synthesis, and BNLF2a mRNA led to immune evasion that prevented T-cell responses to newly infected B cells. Hence, transduced viral RNAs govern critical processes immediately after infection of B cells with EBV and likely play important roles in herpesviral infection in general.

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EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/10/28/jimmunol.090345References

Cited by 92 publications

References 38 publications

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

RNAs in Epstein–Barr virions control early steps of infection

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