scholarly journals Role of NF-κB in Cell Survival and Transcription of Latent Membrane Protein 1-Expressing or Epstein-Barr Virus Latency III-Infected Cells

2004 ◽  
Vol 78 (8) ◽  
pp. 4108-4119 ◽  
Author(s):  
Ellen D. Cahir-McFarland ◽  
Kara Carter ◽  
Andreas Rosenwald ◽  
Jena M. Giltnane ◽  
Sarah E. Henrickson ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Membrane Proteins ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Immunoglobulin M ◽  
Barr Virus ◽  
Epstein Barr ◽  
Germinal Center B Cells

ABSTRACT Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-κB in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-κB, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-κB inhibitor, ΔN-IκBα, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with ΔN-IκBα expression decreased with BAY11 treatment. Newly identified NF-κB-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and IκBε. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1α, MIP1β, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-γRα, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

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.

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4249-4252 ◽  
Author(s):  
Sridhar Chaganti ◽  
Andrew I. Bell ◽  
Noelia Begue Pastor ◽  
Anne E. Milner ◽  
Mark Drayson ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Immunoglobulin Genes ◽  
Barr Virus ◽  
Surface Immunoglobulin ◽  
Epstein Barr ◽  
Transformed Cell Lines ◽  
Germinal Center B Cells

Immunoglobulin genotyping of Epstein-Barr virus (EBV)-positive posttransplantation lymphoproliferative disease has suggested that such lesions often arise from atypical post-germinal center B cells, in some cases carrying functionally inactivated immunoglobulin genes. To investigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in germinal centers (GCs), we isolated GC cells from tonsillar cell suspensions and exposed them to EBV in vitro. Screening more than 100 EBV-transformed cell lines of GC origin identified 6 lines lacking surface immunoglobulin, a phenotype never seen among lines derived from circulating naive or memory B cells. Furthermore, 3 of the 6 surface immunoglobulin-negative GC lines carried inactivating mutations in the immunoglobulin H (IgH) variable gene sequence. The ability of EBV to rescue aberrant products of the germinal center reaction in vitro strengthens the probability that a parallel activity contributes to EBV's lymphomagenic potential in vivo.

scholarly journals An essential role of virus-infected B cells in the marmoset experimental autoimmune encephalomyelitis model

2017 ◽  
Vol 3 (1) ◽  
pp. 205521731769018 ◽  
Author(s):  
Bert A ’t Hart ◽  
Yolanda S Kap
Keyword(s):  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Epstein Barr Virus ◽  
Infection Prevalence ◽  
Autoimmune Encephalomyelitis ◽  
Barr Virus ◽  
Experimental Autoimmune Encephalomyelitis Model ◽  
Epstein Barr ◽  
Experimental Autoimmune

Infection with Epstein–Barr virus (EBV) has been associated with an enhanced risk of genetically susceptible individuals to develop multiple sclerosis (MS). However, an explanation for the contrast between the high EBV infection prevalence (60–90%) and the low MS prevalence (0.1%) eludes us. Here we propose a new concept for the EBV–MS association developed in the experimental autoimmune encephalomyelitis model in marmoset monkeys, which are naturally infected with the EBV-related γ1-herpesvirus CalHV3. The data indicate that the infection of B cells with a γ1-herpesvirus endows them with the capacity to activate auto-aggressive CD8+ T cells specific for myelin oligodendrocyte glycoprotein.

scholarly journals A Tolerogenic Role of Cathepsin G in a Primate Model of Multiple Sclerosis: Abrogation by Epstein–Barr Virus Infection

2020 ◽  
Vol 68 (4) ◽  
Author(s):  
Bert A. ‘t Hart
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Cathepsin G ◽  
Epstein Barr Virus Infection ◽  
Primate Model ◽  
Barr Virus ◽  
Epstein Barr ◽  
Barr Virus Infection

Abstract Using a non-human primate model of the autoimmune neuroinflammatory disease multiple sclerosis (MS), we have unraveled the role of B cells in the making and breaking of immune tolerance against central nervous system myelin. It is discussed here that B cells prevent the activation of strongly pathogenic T cells present in the naïve repertoire, which are directed against the immunodominant myelin antigen MOG (myelin oligodendrocyte glycoprotein). Prevention occurs via destructive processing of a critical epitope (MOG34-56) through the lysosomal serine protease cathepsin G. This effective tolerance mechanism is abrogated when the B cells are infected with Epstein–Barr virus, a ubiquitous γ1-herpesvirus that entails the strongest non-genetic risk factor for MS.

scholarly journals Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease

2017 ◽  
Vol 114 (18) ◽  
pp. 4751-4756 ◽  
Author(s):  
Takeharu Minamitani ◽  
Yijie Ma ◽  
Hufeng Zhou ◽  
Hiroshi Kida ◽  
Chao-Yuan Tsai ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Target Genes ◽  
Nk Cell ◽  
Barr Virus ◽  
Epstein Barr

Epstein–Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.

scholarly journals X-Box-Binding Protein 1 Activates Lytic Epstein-Barr Virus Gene Expression in Combination with Protein Kinase D

2007 ◽  
Vol 81 (14) ◽  
pp. 7363-7370 ◽  
Author(s):  
Prasanna M. Bhende ◽  
Sarah J. Dickerson ◽  
Xiaoping Sun ◽  
Wen-Hai Feng ◽  
Shannon C. Kenney
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
B Cells ◽  
Protein Kinase ◽  
Plasma Cell ◽  
Epstein Barr Virus ◽  
Protein Kinase D ◽  
Plasma Cell Differentiation ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) establishes a latent form of infection in memory B cells, while antibody-secreting plasma cells often harbor the lytic form of infection. The switch between latent and lytic EBV infection is mediated by the two viral immediate-early proteins BZLF1 (Z) and BRLF1 (R), which are not expressed in latently infected B cells. Here we demonstrate that a cellular transcription factor that plays an essential role in plasma cell differentiation, X-box-binding protein 1 (XBP-1), also activates the transcription of the two EBV immediate-early gene promoters. In reporter gene assays, XBP-1 alone was sufficient to activate the R promoter, whereas the combination of XBP-1 and protein kinase D (PKD) was required for efficient activation of the Z promoter. Most importantly, the expression of XBP-1 and activated PKD was sufficient to induce lytic viral gene expression in EBV-positive nasopharyngeal carcinoma cells and lymphoblastoid cells, while an XBP-1 small interfering RNA inhibited constitutive lytic EBV gene expression in lymphoblastoid cells. These results suggest that the plasma cell differentiation factor XBP-1, in combination with activated PKD, can mediate the reactivation of EBV, thereby allowing the viral life cycle to be intimately linked to plasma cell differentiation.

Sign in / Sign up

Export Citation Format

Share Document