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Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells [Batch1]

ABSTRACT: Epidemiological studies have demonstrated that Epstein-Barr virus (EBV) is an etiologic risk factor, and perhaps prerequisite, for the development of MS. EBV establishes life-long latent infection in a subpopulation of memory B cells. Although B cells play a key role in the pathobiology of MS, EBV-associated mechanisms of B cell inflammation and disease pathogenesis in EBV (+) B cells from MS patients are not well characterized. Accordingly, we obtained lymphoblastoid lines (LCLs) and spontaneous LCLs (SLCLs), distinguished by their transformation with lab strain (B95.8) or endogenous EBV, respectively, from MS patients and healthy controls to study host-virus interactions in B cells. Here, we use transcriptomics and genomics-based approaches to identify differences in EBV gene expression and regulation of both viral and cellular genes in LCLs compared to SLCLs and between SLCLs generated from healthy controls and MS patients during “active” or “stable” periods of disease activity. We demonstrate increased lytic gene expression in SLCLs derived from MS patient B cells, especially those generated from peripheral blood mononuclear cells (PBMCs) obtained during “active” disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244312 | GEO | 2024/04/04

REPOSITORIES: GEO

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Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells [Batch3]

Project description:Epidemiological studies have demonstrated that Epstein-Barr virus (EBV) is an etiologic risk factor, and perhaps prerequisite, for the development of MS. EBV establishes life-long latent infection in a subpopulation of memory B cells. Although B cells play a key role in the pathobiology of MS, EBV-associated mechanisms of B cell inflammation and disease pathogenesis in EBV (+) B cells from MS patients are not well characterized. Accordingly, we obtained lymphoblastoid lines (LCLs) and spontaneous LCLs (SLCLs), distinguished by their transformation with lab strain (B95.8) or endogenous EBV, respectively, from MS patients and healthy controls to study host-virus interactions in B cells. Here, we use transcriptomics and genomics-based approaches to identify differences in EBV gene expression and regulation of both viral and cellular genes in LCLs compared to SLCLs and between SLCLs generated from healthy controls and MS patients during “active” or “stable” periods of disease activity. We demonstrate increased lytic gene expression in SLCLs derived from MS patient B cells, especially those generated from peripheral blood mononuclear cells (PBMCs) obtained during “active” disease.

2024-04-04 | GSE244314 | GEO

Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells [Batch2]

2024-04-04 | GSE244313 | GEO

Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells [RNA-Seq]

Project description:Epidemiological studies have demonstrated that Epstein-Barr virus (EBV) is a known etiologic risk factor, and perhaps prerequisite, for the development of MS. EBV establishes life-long latent infection in a subpopulation of memory B cells. Although the role of memory B cells in the pathobiology of MS is well established, studies characterizing EBV-associated mechanisms of B cell inflammation and disease pathogenesis in EBV (+) B cells from MS patients are limited. Accordingly, we analyzed spontaneous lymphoblastoid cell lines (SLCLs) from multiple sclerosis patients and healthy controls to study host-virus interactions in B cells, in the context of an individual’s endogenous EBV. We identify differences in EBV gene expression and regulation of both viral and cellular genes in SLCLs. Our data suggest that EBV latency is dysregulated in MS SLCLs with increased lytic gene expression observed in MS patient B cells, especially those generated from samples obtained during “active” disease. Moreover, we show increased inflammatory gene expression and cytokine production in MS patient SLCLs and demonstrate that tenofovir alafenamide, an antiviral that targets EBV replication, decreases EBV viral loads, EBV lytic gene expression, and EBV-mediated inflammation in both SLCLs and in a mixed lymphocyte assay. Collectively, these data suggest that dysregulation of EBV latency in MS drives a pro-inflammatory, pathogenic phenotype in memory B cells and that this response can be attenuated by suppressing EBV lytic activation. This study provides further support for the development of antiviral agents that target EBV-infection for use in MS.

2023-12-21 | GSE221623 | GEO

Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells [EBV WGS]

Project description:Epstein-Barr virus (EBV) is an etiologic risk factor, and likely prerequisite, for the development of multiple sclerosis (MS). However, the role of EBV infected B cells in the immunopathology of MS is not well understood. Here, we characterized spontaneous lymphoblastoid cell lines (SLCLs) isolated from MS patients and healthy controls (HC) ex vivo to study EBV and host gene expression in the context of an individual’s endogenous EBV. SLCLs derived from MS patient B cells during active disease had higher EBV lytic gene expression than SLCLs from MS patients with stable disease or HCs. Host gene expression analysis revealed activation of pathways associated with hypercytokinemia and interferon signaling in MS SLCLs and differential expression of several genes, including upregulation of forkhead box protein 1 (FOXP1), which contributes to EBV lytic gene expression. In addition, we demonstrate that antiviral approaches targeting EBV replication decreased inflammatory cytokine production and diminished autologous CD4+ T cell responses. These data suggest that dysregulation of intrinsic B-cell control of EBV gene expression drives a pro-inflammatory, pathogenic B cell phenotype that can be attenuated by suppressing EBV lytic gene expression.

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Project description:Epstein-Barr virus (EBV) is a human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. To date, a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs in viral pathogenesis is not well defined. Here, we used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deep sequencing and computational analysis to comprehensively examine the viral and cellular miRNA targetome in EBV B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 3'UTRs. 531 of these sites contained seed-matches to viral miRNAs. 24 PAR-CLIP-identified miRNA:3'UTR interactions were confirmed by reporter assays. Our results reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, thereby manipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellular processes that are directly relevant to viral infection, including innate immunity, cell survival, and cell proliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. This comprehensive survey of the miRNA targetome in EBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, and potentially, identifying novel therapeutic targets for EBVassociated malignancies. Ago2 (Argonaute 2) PAR-CLIP and small RNA deep sequencing of Epstein-Barr virus B95.8-infected lymphoblastoid cell lines (LCLs).

2012-10-16 | E-GEOD-41437 | biostudies-arrayexpress

Transcription profiling by array of human lymphocyte cells lines generated with EBNA3-knockout Epstein-Barr Viruses

Project description:Epstein-Barr virus (EBV) is able to drive the transformation of B-cells, resulting in the generation of lymphocyte cell lines (LCLs) in vitro. EBV nuclear proteins EBNA3A and EBNA3C are necessary for efficient transformation, while EBNA3B is dispensable. We describe a transcriptome analysis of LCLs generated with EBNA3B knockout (3BKO) EBV (made in the B95-8 BAC generated by Delecluse and Hammerschmidt) and comparable LCLs made with the parental B95-8 BAC (wtBAC).<br>Peripheral blood cells from three donors were infected with two 3BKO virus preparations, and two wtBAC virus preps. LCLs were grown out, and RNA extracted after 3-6 weeks (depending how long the outgrowth took). Total RNA was ribominus treated and then labelled and hybridised to Affymetrix human exon 1.0ST microarrays.

2010-10-30 | E-MEXP-2768 | biostudies-arrayexpress

microRNA expression data from human platelets infected by EBV in vitro

Project description:Viruses can directly interact with platelets and modulate their function. Viral impact on platelet activation, and platelet-mediated modulations of innate and adaptive immune responses. Human herpesvirus 4, also known as Epstein–Barr virus (EBV) interaction with platelets occurs via complement receptor 2 (CR2), but the exact mechanism of action with platelets is still poorly understood. Epstein–Barr virus (EBV), is extremely efficient at establishing a persistent life-long infection in human B cells. In the present study, GeneChips were performed in human platelets from three normal donors infected with the EBV-containing supernatant of the B95.8 marmoset cell line in vitro.

2022-01-01 | GSE181075 | GEO

Gene expression data from human platelets infected by EBV in vitro

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Gene expression profiling of the response to interferon beta in EBV-transformed and primary B cells of patients with multiple sclerosis

Project description:To identify gene expression changes and pathways induced by interferon-? (IFN-?) in B cells, we studied the in vitro response of EBV-transformed B cells (lymphoblast cell lines-LCLs). LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-? exposure, with over 50 novel IFN-? response genes. Pathways analysis demonstrated that IFN-? affected LCLs in a similar manner to other cell types by activating known IFN-? canonical pathways. Additionally, IFN-? increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Several of the novel response genes were tested and validated as IFN-? response genes in human primary B cells. Total RNA from LCL samples treated for four hours with interferon beta (100u/ml) was compared to RNA from untreated LCLs (paired analysis). LCL samples were from patients with MS.

2014-07-30 | E-GEOD-58240 | biostudies-arrayexpress

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