scholarly journals Caspases switch off m6A RNA modification pathway to reactivate a ubiquitous human tumor virus

2020 ◽  
Author(s):  
Kun Zhang ◽  
Yucheng Zhang ◽  
Jun Wan ◽  
Renfeng Li
Keyword(s):  
Human Tumor ◽  
Feedback Regulation ◽  
Rna Modification ◽  
Barr Virus ◽  
Multiple Components ◽  
Tumor Virus ◽  
Epstein Barr ◽  
Caspase Substrate

AbstractThe methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Together, our study establishes that caspase disarming of the m6A RNA modification machinery fosters EBV reactivation.

scholarly journals Epstein-Barr virus reprograms human B-lymphocytes immediately in the pre-latent phase of infection

2018 ◽  
Author(s):  
Paulina Mrozek-Gorska ◽  
Alexander Buschle ◽  
Dagmar Pich ◽  
Thomas Schwarzmayr ◽  
Ron Fechtner ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Metabolic Pathways ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Time Resolved ◽  
Barr Virus ◽  
Tumor Virus ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B-lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV’s oncogenic potential in vivo. This seminal finding was made 50 years ago, but how EBV activates primary human B-lymphocytes and how lymphoblastoid cell lines (LCLs) evolve from the EBV-infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B-lymphocytes. EBV reprograms these human cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 hours of infection and precede any metabolic and phenotypic changes. Within the next 48 hours, the virus activates the cells, changes their phenotypes with respect to cell size, RNA and protein content and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day three post infection. The transcriptional program that EBV initiates consists of three waves of clearly discernable clusters of cellular genes that peak on day one, two, or three and regulate RNA synthesis, metabolic pathways and cell division, respectively. Upon the onset of cell doublings on day four the cellular transcriptome appears to be completely reprogrammed to support the activated and proliferating cell, but three additional clusters of EBV regulated genes adjust the infected immune cells to fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 98 % of the 13,000 expressed genes in B-lymphocytes are regulated upon infection demonstrating that EBV governs the entire biology of its target cell.

scholarly journals Epstein–Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection

2019 ◽  
Vol 116 (32) ◽  
pp. 16046-16055 ◽  
Author(s):  
Paulina Mrozek-Gorska ◽  
Alexander Buschle ◽  
Dagmar Pich ◽  
Thomas Schwarzmayr ◽  
Ron Fechtner ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Metabolic Pathways ◽  
Epstein Barr Virus ◽  
Plasma Cells ◽  
Human Tumor ◽  
Proliferating Cells ◽  
Barr Virus ◽  
Epstein Barr

Epstein–Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV’s oncogenic potential in vivo. How lymphoblastoid cell lines (LCLs) evolve from the infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B lymphocytes. EBV reprograms the cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 h and precede any metabolic and phenotypic changes. Within 72 h, the virus activates the cells, changes their phenotypes with respect to cell size, RNA, and protein content, and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day 3 postinfection. The transcriptional program that EBV initiates consists of 3 waves of clearly discernable clusters of cellular genes that peak on day 2, 3, or 4 and regulate RNA synthesis, metabolic pathways, and cell division, respectively. Upon onset of cell doublings on day 4, the cellular transcriptome appears to be completely reprogrammed to support the proliferating cells, but 3 additional clusters of EBV-regulated genes fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 11,000 genes are regulated upon EBV infection as naïve B cells exit quiescence to enter a germinal center-like differentiation program, which culminates in immortalized, proliferating cells that partially resemble plasmablasts and early plasma cells.

EBV+ Lymphoproliferative Diseases: Opportunities for leveraging EBV as a Therapeutic Target

Blood ◽  
2021 ◽  
Author(s):  
Keri Toner ◽  
Catherine M. Bollard
Keyword(s):  
Proliferative Response ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Lymphoproliferative Disease ◽  
Lymphoproliferative Diseases ◽  
Malignant Lymphomas ◽  
Barr Virus ◽  
Immune Therapies ◽  
Tumor Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell based immune therapies. In this review, we will describe the EBV-associated lymphoproliferative diseases and will particularly focus on the therapies that target EBV.

scholarly journals Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Yonggang Pei ◽  
Josiah Hiu-yuen Wong ◽  
Hem Chandra Jha ◽  
Tian Tian ◽  
Zhi Wei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Population ◽  
Regulatory Networks ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Human Tumor ◽  
Barr Virus ◽  
Repressor Complex ◽  
Tumor Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) was discovered as the first human tumor virus more than 50 years ago. EBV infects more than 90% of the human population worldwide and is associated with numerous hematologic malignancies and epithelial malignancies. EBV establishes latent infection in B cells, which is the typical program seen in lymphomagenesis. Understanding EBV-mediated transcription regulatory networks is one of the current challenges that will uncover new insights into the mechanism of viral-mediated lymphomagenesis. Here, we describe the regulatory profiles of several cellular factors (E2F6, E2F1, Rb, HDAC1, and HDAC2) together with EBV latent nuclear antigens using next-generation sequencing (NGS) analysis. Our results show that the E2F-Rb-HDAC complex exhibits similar distributions in genomic regions of EBV-positive cells and is associated with oncogenic super-enhancers involving long-range regulatory regions. Furthermore, EBV latent antigens cooperatively hijack this complex to bind at KLFs gene loci and facilitate KLF14 gene expression in lymphoblastoid cell lines (LCLs). These results demonstrate that EBV latent antigens can function as master regulators of this multisubunit repressor complex (E2F-Rb-HDAC) to reverse its suppressive activities and facilitate downstream gene expression that can contribute to viral-induced lymphomagenesis. These results provide novel insights into targets for the development of new therapeutic interventions for treating EBV-associated lymphomas. IMPORTANCE Epstein-Barr virus (EBV), as the first human tumor virus, infects more than 90% of the human population worldwide and is associated with numerous human cancers. Exploring EBV-mediated transcription regulatory networks is critical to understand viral-associated lymphomagenesis. However, the detailed mechanism is not fully explored. Now we describe the regulatory profiles of the E2F-Rb-HDAC complex together with EBV latent antigens, and we found that EBV latent antigens cooperatively facilitate KLF14 expression by antagonizing this multisubunit repressor complex in EBV-positive cells. This provides potential therapeutic targets for the treatment of EBV-associated cancers.

Transient Immunodeficiency During Asymptomatic Epstein-Barr Virus Infection

PEDIATRICS ◽  
1983 ◽  
Vol 71 (6) ◽  
pp. 964-967
Author(s):  
THOMAS J. BOWEN ◽  
RALPH J. WEDGWOOD ◽  
HANS D. OCHS ◽  
WERNER HENLE
Keyword(s):  
Epstein Barr Virus ◽  
Mononuclear Cells ◽  
Epstein Barr Virus Infection ◽  
Peripheral Blood Mononuclear ◽  
Immunoglobulin Synthesis ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

In vivo and in vitro humoral and cellular immune responses were studied in a 2½-year-old girl immediately before, during, and after an asymptomatic infection with Epstein-Barr virus. During the acute EBV infection, the patient's peripheral blood mononuclear cells were deficient in immunoglobulin synthesis and suppressed the in vitro immunoglobulin synthesis of normal allogeneic cells. In vitro mitogen transformation of lymphocytes was reduced. In vivo antibody responses to the T cell-dependent antigens bacteriophage φX 174 and Keyhole limpet hemocyanin were markedly depressed. These studies suggest that suppressor cells induced during acute EBV infection not only suppress immunoglobulin synthesis in vitro, but also interfere with in vivo antibody synthesis.

scholarly journals Development of suppressor T lymphocytes for Epstein-Barr virus-induced B-lymphocyte outgrowth during acute infectious mononucleosis: assessment by two quantitative systems

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 510-517 ◽  
Author(s):  
RT Schooley ◽  
BF Haynes ◽  
J Grouse ◽  
C Payling-Wright ◽  
AS Fauci ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
B Lymphocyte ◽  
Acute Stage ◽  
Cell Mediated Immunity ◽  
Barr Virus ◽  
Epstein Barr

Abstract A system of 3H-thymidine incorporation by lymphocytes in culture for 3 wk has been utilized for quantitative assessment of the ability of T lymphocytes to inhibit outgrowth of autologous Epstein-Barr virus (EBV) transformed B lymphocytes. Lymphocytes from EBV-seronegative individuals lack the ability to suppress outgrowth of autologous EBV- transformed B lymphocytes. This capability appears during the course of primary EBV-induced infectious mononucleases (IM) as the atypical lymphocytosis is subsiding and persists for years after recovery from primary EBV infection. The ability of T lymphocytes from EBV- seropositive subjects or convalescent IM patients to inhibit B- lymphocyte outgrowth is not HLA restricted. Thus, T lymphocytes capable of inhibition of in vitro EBV-induced B-cell outgrowth emerge during the acute stage of IM and may represent an important control mechanism of EBV-induced B-lymphocyte proliferation in vivo. The system provides a highly sensitive quantitative means for in vitro assessment of cell- mediated immunity to EBV.

scholarly journals Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

2006 ◽  
Vol 81 (3) ◽  
pp. 1195-1208 ◽  
Author(s):  
Chih-Chung Lu ◽  
Ho-Ting Huang ◽  
Jiin-Tarng Wang ◽  
Geir Slupphaug ◽  
Tsai-Kun Li ◽  
...  
Keyword(s):  
Dna Replication ◽  
Epstein Barr Virus ◽  
Efficient Production ◽  
Transcription Activator ◽  
Viral Dna ◽  
Barr Virus ◽  
Epstein Barr ◽  
Lytic Dna Replication

ABSTRACT Uracil-DNA glycosylases (UDGs) of the uracil-N-glycosylase (UNG) family are the primary DNA repair enzymes responsible for removal of inappropriate uracil from DNA. Recent studies further suggest that the nuclear human UNG2 and the UDGs of large DNA viruses may coordinate with their DNA polymerase accessory factors to enhance DNA replication. Based on its amino acid sequence, the putative UDG of Epstein-Barr virus (EBV), BKRF3, belongs to the UNG family of proteins, and it was demonstrated previously to enhance oriLyt-dependent DNA replication in a cotransfection replication assay. However, the expression and enzyme activity of EBV BKRF3 have not yet been characterized. In this study, His-BKRF3 was expressed in bacteria and purified for biochemical analysis. Similar to the case for the Escherichia coli and human UNG enzymes, His-BKRF3 excised uracil from single-stranded DNA more efficiently than from double-stranded DNA and was inhibited by the purified bacteriophage PBS1 inhibitor Ugi. In addition, BKRF3 was able to complement an E. coli ung mutant in rifampin and nalidixic acid resistance mutator assays. The expression kinetics and subcellular localization of BKRF3 products were detected in EBV-positive lymphoid and epithelial cells by using BKRF3-specific mouse antibodies. Expression of BKRF3 is regulated mainly by the immediate-early transcription activator Rta. The efficiency of EBV lytic DNA replication was slightly affected by BKRF3 small interfering RNA (siRNA), whereas cellular UNG2 siRNA or inhibition of cellular and viral UNG activities by expressing Ugi repressed EBV lytic DNA replication. Taking these results together, we demonstrate the UNG activity of BKRF3 in vitro and in vivo and suggest that UNGs may participate in DNA replication or repair and thereby promote efficient production of viral DNA.

scholarly journals Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen

2005 ◽  
Vol 79 (12) ◽  
pp. 7355-7362 ◽  
Author(s):  
Michelle A. Swanson-Mungerson ◽  
Robert G. Caldwell ◽  
Rebecca Bultema ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Barr Virus ◽  
Low Levels ◽  
Epstein Barr

ABSTRACT A significant percentage of the population latently harbors Epstein-Barr virus (EBV) in B cells. One EBV-encoded protein, latent membrane protein 2A (LMP2A), is expressed in tissue culture models of EBV latent infection, in human infections, and in many of the EBV-associated proliferative disorders. LMP2A constitutively activates proteins involved in the B-cell receptor (BCR) signal transduction cascade and inhibits the antigen-induced activation of these proteins. In the present study, we investigated whether LMP2A alters B-cell receptor signaling in primary B cells in vivo and in vitro. LMP2A does not inhibit antigen-induced tolerance in response to strong stimuli in an in vivo tolerance model in which B cells are reactive to self-antigen. In contrast, LMP2A bypasses anergy induction in response to low levels of soluble hen egg lysozyme (HEL) both in vivo and in vitro as determined by the ability of LMP2A-expressing HEL-specific B cells to proliferate and induce NF-κB nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-κB nuclear translocation independent of BCR cross-linking. Since NF-κB is required to bypass tolerance induction, this LMP2A-dependent NF-κB activation may complete the tolerogenic signal induced by low levels of soluble HEL. Overall, the findings suggest that LMP2A may not inhibit BCR-induced signals under all conditions as previously suggested by studies with EBV immortalized B cells.

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