scholarly journals Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions

2019 ◽  
Vol 21 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Lawrence T. C. Ong ◽  
Grant P. Parnell ◽  
Ali Afrasiabi ◽  
Graeme J. Stewart ◽  
Sanjay Swaminathan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
B Cells ◽  
Epstein Barr Virus ◽  
B Lymphocyte ◽  
Sequencing Data ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Activated B Cells

Abstract Epstein–Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines—LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.

scholarly journals Identification of Host Biomarkers of Epstein-Barr Virus Latency IIb and Latency III

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Joshua E. Messinger ◽  
Joanne Dai ◽  
Lyla J. Stanland ◽  
Alexander M. Price ◽  
Micah A. Luftig
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Single Cell Analysis ◽  
Viral Gene Expression ◽  
Molecular Pathogenesis ◽  
Viral Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACTDeciphering the molecular pathogenesis of virally induced cancers is challenging due, in part, to the heterogeneity of both viral gene expression and host gene expression. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus prevalent in B-cell lymphomas of immune-suppressed individuals. EBV infection of primary human B cells leads to their immortalization into lymphoblastoid cell lines (LCLs), serving as a model of these lymphomas. In previous studies, reports from our laboratory have described a temporal model for immortalization with an initial phase characterized by expression of Epstein-Barr nuclear antigens (EBNAs), high levels of c-Myc activity, and hyperproliferation in the absence of the latent membrane proteins (LMPs), called latency IIb. This is followed by the long-term outgrowth of LCLs expressing the EBNAs along with the LMPs, particularly NFκB-activating LMP1, defining latency III. However, LCLs express a broad distribution of LMP1 such that a subset of these cells express LMP1 at levels similar to those seen in latency IIb, making it difficult to distinguish these two latency states. In this study, we performed mRNA sequencing (mRNA-Seq) on early EBV-infected latency IIb cells and latency III LCLs sorted by NFκB activity. We found that latency IIb transcriptomes clustered independently from latency III independently of NFκB. We identified and validated mRNAs defining these latency states. Indeed, we were able to distinguish latency IIb cells from LCLs expressing low levels of LMP1 using multiplex RNA-fluorescencein situhybridization (RNA-FISH) targeting EBVEBNA2orLMP1and humanCCR7orMGST1. This report defines latency IIb as a bona fide latency state independent from latency III and identifies biomarkers for understanding EBV-associated tumor heterogeneity.IMPORTANCEEBV is a ubiquitous pathogen, with >95% of adults harboring a life-long latent infection in memory B cells. In immunocompromised individuals, latent EBV infection can result in lymphoma. The established expression profile of these lymphomas is latency III, which includes expression of all latency genes. However, single-cell analysis of EBV latent gene expression in these lymphomas suggests heterogeneity where most cells express the transcription factor, EBNA2, and only a fraction of the cells express membrane protein LMP1. Our work describes an early phase after infection where the EBNAs are expressed without LMP1, called latency IIb. However, LMP1 levels within latency III vary widely, making these states hard to discriminate. This may have important implications for therapeutic responses. It is crucial to distinguish these states to understand the molecular pathogenesis of these lymphomas. Ultimately, better tools to understand the heterogeneity of these cancers will support more-efficacious therapies in the future.

scholarly journals Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain

2007 ◽  
Vol 204 (12) ◽  
pp. 2899-2912 ◽  
Author(s):  
Barbara Serafini ◽  
Barbara Rosicarelli ◽  
Diego Franciotta ◽  
Roberta Magliozzi ◽  
Richard Reynolds ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Plasma Cells ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Postmortem Brain Tissue ◽  
Epstein Barr

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, has been associated with multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), but direct proof of its involvement in the disease is still missing. To test the idea that MS might result from perturbed EBV infection in the CNS, we investigated expression of EBV markers in postmortem brain tissue from MS cases with different clinical courses. Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8+ T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells. Whether homing of EBV-infected B cells to the CNS is a primary event in MS development or the consequence of a still unknown disease-related process, we interpret these findings as evidence that EBV persistence and reactivation in the CNS play an important role in MS immunopathology.

scholarly journals The Interaction of Human and Epstein–Barr Virus miRNAs with Multiple Sclerosis Risk Loci

2021 ◽  
Vol 22 (6) ◽  
pp. 2927
Author(s):  
Ali Afrasiabi ◽  
Nicole L. Fewings ◽  
Stephen D. Schibeci ◽  
Jeremy T. Keane ◽  
David R. Booth ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Epstein Barr Virus ◽  
In Vitro Assays ◽  
Potential Contribution ◽  
Barr Virus ◽  
Ebv Infection ◽  
Protective Allele ◽  
Epstein Barr ◽  
Ms Pathogenesis

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly.

scholarly journals Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeremy T. Keane ◽  
Ali Afrasiabi ◽  
Stephen D. Schibeci ◽  
Nicole Fewings ◽  
Grant P. Parnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Gender Differences ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Risk Gene ◽  
Gender Specific Differences ◽  
Epstein Barr ◽  
Gender Specific

Multiple Sclerosis (MS) is a complex immune-mediated disease of the central nervous system. Treatment is based on immunomodulation, including specifically targeting B cells. B cells are the main host for the Epstein-Barr Virus (EBV), which has been described as necessary for MS development. Over 200 genetic loci have been identified as increasing susceptibility to MS. Many MS risk genes have altered expression in EBV infected B cells, dependent on the risk genotype, and are themselves regulated by the EBV transcription factor EBNA2. Females are 2-3 times more likely to develop MS than males. We investigated if MS risk loci might mediate the gender imbalance in MS. From a large public dataset, we identified gender-specific associations with EBV traits, and MS risk SNP/gene pairs with gender differences in their associations with gene expression. Some of these genes also showed gender differences in correlation of gene expression level with Estrogen Receptor 2. To test if estrogens may drive these gender specific differences, we cultured EBV infected B cells (lymphoblastoid cell lines, LCLs), in medium depleted of serum to remove the effects of sex hormones as well as the estrogenic effect of phenol red, and then supplemented with estrogen (100 nM estradiol). Estradiol treatment altered MS risk gene expression, LCL proliferation rate, EBV DNA copy number and EBNA2 expression in a sex-dependent manner. Together, these data indicate that there are estrogen-mediated gender-specific differences in MS risk gene expression and EBV functions. This may in turn contribute to gender differences in host response to EBV and to MS susceptibility.

scholarly journals Epstein-Barr Virus and Multiple Sclerosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Gunnar Houen ◽  
Nicole Hartwig Trier ◽  
Jette Lautrup Frederiksen
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Clinical Signs ◽  
Oligoclonal Bands ◽  
Barr Virus ◽  
Ebv Infection ◽  
First Line Therapy ◽  
Epstein Barr ◽  
Myelinated Nerves

Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV’s role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.

scholarly journals Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Takaya Ichikawa ◽  
Yusuke Okuno ◽  
Yoshitaka Sato ◽  
Fumi Goshima ◽  
Hironori Yoshiyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Cycle ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Progeny Production ◽  
Barr Virus ◽  
Ebv Infection ◽  
Histone H3k27 ◽  
Epstein Barr

ABSTRACTEpigenetic modifications play a pivotal role in the expression of the genes of Epstein-Barr virus (EBV). We found thatde novoEBV infection of primary B cells caused moderate induction of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase. To investigate the role of EZH2, we knocked out the EZH2 gene in EBV-negative Akata cells by the CRISPR/Cas9 system and infected the cells with EBV, followed by selection of EBV-positive cells. During the latent state, growth of EZH2-knockout (KO) cells was significantly slower after infection compared to wild-type controls, despite similar levels of viral gene expression between cell lines. After induction of the lytic cycle by anti-IgG, KO of EZH2 caused notable induction of expression of both latent and lytic viral genes, as well as increases in both viral DNA replication and progeny production. These results demonstrate that EZH2 is crucial for the intricate epigenetic regulation of not only lytic but also latent gene expression in Akata cells.IMPORTANCEThe life cycle of EBV is regulated by epigenetic modifications, such as CpG methylation and histone modifications. Here, we found that the expression of EZH2, which encodes a histone H3K27 methyltransferase, was induced by EBV infection; therefore, we generated EZH2-KO cells to investigate the role of EZH2 in EBV-infected Akata B cells. Disruption of EZH2 resulted in increased expression of EBV genes during the lytic phase and, therefore, efficient viral replication and progeny production. Our results shed light on the mechanisms underlying reactivation from an epigenetic point of view and further suggest a role for EZH2 as a form of innate immunity that restricts viral replication in infected cells.

scholarly journals B cells infected with Type 2 Epstein-Barr virus (EBV) have increased NFATc1/NFATc2 activity and enhanced lytic gene expression in comparison to Type 1 EBV infection

2020 ◽  
Vol 16 (2) ◽  
pp. e1008365 ◽  
Author(s):  
James C. Romero-Masters ◽  
Shane M. Huebner ◽  
Makoto Ohashi ◽  
Jillian A. Bristol ◽  
Bayleigh E. Benner ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Lytic Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lytic Gene Expression ◽  
Epstein Barr

scholarly journals Effects of Epstein-Barr Virus Infection on CD19+ B Lymphocytes in Patients with Immunorelated Pancytopenia

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yang Zhao ◽  
Yihao Wang ◽  
Hui Liu ◽  
Kai Ding ◽  
Chunyan Liu ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
B Lymphocyte ◽  
Enzyme Linked Immunosorbent Assay ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ebv Dna ◽  
Epstein Barr

Objectives. To explore effects of Epstein-Barr virus (EBV) infection on CD19+ B lymphocytes in patients with immunorelated pancytopenia (IRP). Methods. An enzyme-linked immunosorbent assay (ELISA) in vitro diagnostic kit was used to detect EBV capsid antigen- (CA-) IgG and VCA-IgM antibodies in the serum. We analyzed the EBV-DNA copies of CD19+ B lymphocyte by using real-time quantitative polymerase chain reaction (RT-qPCR). CD21, CD23, CD5, CD80, and CD86 receptors on the surfaces of CD19+ B cells were detected by flow cytometry (FCM). The correlation between these receptors and EBV-DNA copies were evaluated. Results. The results revealed that the positive rate of EBVCA-IgM and CD19+ B lymphocyte EBV-DNA copy in the IRP group were significantly higher than those in the control group (P<0.05). CD19+ B lymphocyte EBV-DNA copies were also more abundant in IRP patients than in control subjects (P<0.05). Expression levels of the CD21, CD23, CD5, CD80, and CD86 receptors on the surfaces of CD19+ B cells in IRP patients with anti-EBVCA IgM positivity were significantly higher than those in anti-EBVCA IgM negativity IRP patients (P<0.05). The results revealed that EBV-DNA copy numbers were positively correlated with CD21, CD23, CD5, CD80, and CD86 expression. Conclusions. EBV infection may activate CD19+ B lymphocytes and further disrupt bone marrow hematopoiesis in IRP patients.

scholarly journals Robust T-cell stimulation by Epstein-Barr virus–transformed B cells after antigen targeting to DEC-205

Blood ◽  
2013 ◽  
Vol 121 (9) ◽  
pp. 1584-1594 ◽  
Author(s):  
Carol S. Leung ◽  
Michael A. Maurer ◽  
Sonja Meixlsperger ◽  
Anne Lippmann ◽  
Cheolho Cheong ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Cell Stimulation ◽  
Barr Virus ◽  
T Cell Stimulation ◽  
Key Points ◽  
Epstein Barr ◽  
Mhc Presentation ◽  
Activated B Cells

Key Points B cells contribute to MHC presentation of DEC-205–targeted antigen. Activated B cells present DEC-205–targeted antigen efficiently, because they retain it longer.

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