EBV induces CNS homing of B cells attracting inflammatory T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE299939 | GEO | 2025/07/07
REPOSITORIES: GEO
Similar Datasets
Project description:Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) onset and plays an etiologic role in the disease, although the nature of viral involvement is poorly understood. A common early event in the course of MS is Clinically Isolated Syndrome (CIS), a neuroinflammatory demyelinating condition for which 60-80% of cases progress to relapsing-remitting MS (RRMS). To investigate possible viral pathogenesis during early disease stages, we analyzed single-cell gene and surface protein expression of CIS peripheral B cells collected longitudinally during the Immune Tolerance Network (ITN) STAyCIS Trial. CIS B cell profiles were compared to publicly available scRNA-seq data from in vitro EBV infection, other autoimmune disorders, chronic infectious diseases, and healthy controls. Analyses focused on CD19+/CD20+/CD21lo/CD11c+/T-bet+ atypical B cells (ABCs), which are expanded pathogenic effectors in MS and other autoimmune and chronic infectious diseases. CIS PBMCs contained significantly higher frequencies of ABCs than healthy adult controls by scRNA-seq and flow cytometry, establishing ABC compartment expansion as a clinical feature of CIS. An EBV-associated ABC transcriptome, including expression of CXCR3 and immune checkpoint molecules (PD-L1, PD-L2), was enriched in CIS versus controls; however, evidence of direct EBV infection within the ABC niche was infrequently observed. CIS ABCs exhibited significant enrichment of inflammatory cytokine mRNAs including CXCL8 (IL8), IL18, and VEGFA. Several of these cytokines (IL-8, VEGF) were secreted by B cells upon de novo EBV exposure. CIS outcome stratification revealed a rare yet distinctive inflammatory ABC signature significantly underrepresented in long-term non-progressors (LTNP) versus people with primary endpoint RRMS activity. Moreover, CXCR3+ ABCs increased after baseline CIS diagnosis and were significantly enriched in MS vs LTNP outcomes after controlling for age and sex. Thus, we find evidence for ABC expansion, inflammatory responses, and checkpoint that precede MS onset, possibly as a bystander response to EBV infection.
2025-05-27 | GSE267750 | GEO
Project description:EBV induces CNS homing of B cells attracting inflammatory T cells
| PRJNA1277578 | ENA
Project description:<p>Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD <em>de novo</em> biosynthesis by driving expression of the host metabolic enzyme IDO1. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is thus a druggable metabolic vulnerability of EBV-driven B cell transformation – opening therapeutic possibilities for EBV-related diseases.</p>
2024-04-29 | MTBLS2243 | MetaboLights
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
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
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 | GSE244313 | GEO
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 | GSE244312 | GEO
Project description:Genome wide association studies have identified >200 susceptibility loci accounting for much of the heritability of Multiple Sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. Methods: We have investigated transcriptomes of B cells and EBV infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection
2019-04-01 | GSE126379 | GEO
Project description:Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM)) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).cell infection to investigate the underlying mechanisms that control EBV-induced B-cell immortalization. ATAC-seq revealed that over a third of accessible chromatin is altered with the most perturbed sites overlapping Ets-family, including PU.1 and RUNX1 transcription factors. EBV nuclear antigens (EBNAs) clustered with different gene categories and RNA-seq identified the transcriptional response of these gene. Focusing on EBNA1 revealed a selection of gene targets involved in nucleotide metabolism. Metabolomics indicated that adenosine and purine metabolism are significantly altered by EBV immortalization, and we validated that adenosine deaminase (ADA) is a direct and critical target of EBNA1 and the EBV-directed immortalization process. These findings reveal that purine metabolism and ADA inhibitors may be a useful therapeutic for EBV-driven lymphoid cancers
2021-05-05 | GSE172475 | GEO
Project description:Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM)) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).cell infection to investigate the underlying mechanisms that control EBV-induced B-cell immortalization. ATAC-seq revealed that over a third of accessible chromatin is altered with the most perturbed sites overlapping Ets-family, including PU.1 and RUNX1 transcription factors. EBV nuclear antigens (EBNAs) clustered with different gene categories and RNA-seq identified the transcriptional response of these gene. Focusing on EBNA1 revealed a selection of gene targets involved in nucleotide metabolism. Metabolomics indicated that adenosine and purine metabolism are significantly altered by EBV immortalization, and we validated that adenosine deaminase (ADA) is a direct and critical target of EBNA1 and the EBV-directed immortalization process. These findings reveal that purine metabolism and ADA inhibitors may be a useful therapeutic for EBV-driven lymphoid cancers
2021-05-05 | GSE172476 | GEO