Epstein–Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling

Samanta, Mrinal; Iwakiri, Dai; Takada, Kenzo

doi:10.1038/onc.2008.75

Cited by 152 publications

(111 citation statements)

References 33 publications

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“…We observed that TLR3 responses for IL-6 secretion were low in primary B cells and abolished in LCLs. Discrepancies between our findings and those reported in terms of TLR3 activity could deviate from the cellular models used, and the time points postinfection chosen for expression and functionality studies (39,40). Most strikingly, TLR5 functionality was halted in our EBV-infected cells; although there are no reports correlating TLR5 to EBV, this observation merits further investigation.…”

Section: Discussioncontrasting

confidence: 48%

EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

Fathallah

Parroche²,

Gruffat³

et al. 2010

The Journal of Immunology

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Section: Discussioncontrasting

confidence: 48%

EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

Fathallah

Parroche²,

Gruffat³

et al. 2010

The Journal of Immunology

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“…Indeed, chronic activation of antiviral immunity by erroneous detection of extracellular RNA drives autoimmunity in predisposed individuals (20). Although binding of proinflammatory EBERs to cytoplasmic sensors has been reported in vitro (9)(10)(11)(12), there is little evidence that this may occur in latently infected B cells in a physiologically relevant context (21), but there are multiple indications that EBERs are secreted from infected cells (9,22,23).…”

Section: Significancementioning

confidence: 99%

“…Both double-stranded loops and the uncapped 5′-triphosphate terminus of EBERs serve as ligands for pathogen recognition receptors (PRRs) (9)(10)(11)(12). Because infected individuals (estimated at 90% of the world population) generally have no symptoms, it seems that EBER production in healthy individuals elude cell-intrinsic danger signaling.…”

Section: Significancementioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

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

144

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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“…Another evidence of a role of EBERs in innate immunity is their binding to Toll-like receptor 3 after secreted from EBV-infected cells (Iwakiri et al, 2009;Iwakiri and Takada, 2010), triggering innate immunity that might explain immunopathologic diseases caused by active EBV infection. However, EBERs also induce an anti-infl ammatory cytokine, IL-10, through RIG-1-mediated interferon regulatory factor (IRF) 3 (Samanta et al, 2008), suggesting that modulation of innate immune signaling by EBERs may contribute to EBVmediated oncogenesis.…”

Section: Treatment Strategies For the Patients With Ebv-associated Chlmentioning

confidence: 99%

“…Nt (Ho et al, 1999;Komano et al, 1999;Kitagawa et al, 2000;Yamamoto et al., 2000;Iwakiri et al, 2003;Iwakiri et al, 2005;Samanta et al, 2006;Samanta et al, 2008;Iwakiri et al, 2009;Iwakiri and Takada, 2010 Immunization with LMP1 gene or polyepitope expression vectors Taylor et al, 2004;Smith et al, 2006;Pan et al, 2009;Lutzky et al, 2010;Chia et al, Immunization with LMP2A gene or polyepitope expression vectors (Taylor et al, 2004;Smith et al, 2006;Pan et al, 2009;Lutzky et al, 2010;Chia et al, 2011) LMP2B Modulation of innate immune response nt TLR: Toll-like receptor, RIG: retinoic acid-inducible gene, PKR: RNA-dependent protein kinase, Nt: not tested, CTL: cytotoxic T lymphocyte, DC: dendritic cells.…”

Section: Inhibition Of Apoptosis (Pkr)mentioning

confidence: 99%

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

Lee¹

2011

Biomolecules and Therapeutics

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Lymphoma is a type of cancer involving cells of the immune system, and has two major categories: Hodgkin lymphoma (HL) and all other lymphomas (non-HL). Although the two types may display the same symptoms, they are readily distinguishable via microscopic examination, and differ in the way they develop, spread and are treated. HL is a unique clinicopathological disorder characterized by the rare presence of malignant cells (usually accounting for 0.1% to 10% of the cells in the total tumor mass) in a background of a nonneoplastic cellular microenvironment comprising T-and Blymphocytes and other cell types (Weiss et al., 1999). In the United States, about 8,500 new cases of HL were expected to be diagnosed in 2010, and the overall incidence is increasing each year (Maggioncalda et al., 2011).Although the pathogenesis of HL is still largely unknown, the association of HL with Epstein-Barr virus (EBV) infection has been demonstrated in many reports. For examples, HL patients show elevated antibody titers to EBV antigens (Levine et al., 1971), and the risk of developing HL is increased up to three-fold in population that have experienced infectious mononucleosis caused by primary EBV infection (Gutensohn Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBVassociated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event in the development of this disease, EBV infection may play a very crucial role in the pathogenesis of HL. AbstractAccording to a population-based cohort study, the frequency of EBV associated HL among total HL cases varies from 30 to 50% (in certain cases even higher; >90% in developing and underdeveloped countries, and >95% in HIV associated cases), and most of them appear in classical Hodgkin lymphoma (cHL), the major type of HL (Herbst et al., 1991;Pallesen et al., 1991;Ambinder et al., 1993;Leoncini et al., 1996). Since EBV is an oncogenic virus that is able to subvert cellular processes supporting growth and survival, the approach to unravel the f...

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Epstein–Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling

Cited by 152 publications

References 33 publications

EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

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