scholarly journals Epstein–Barr Virus: Should We Still Invest in Vaccines or Focus on Predictive Tests?

2021 ◽  
Author(s):  
Emmanuel Drouet
Keyword(s):  
Immune System ◽  
Epithelial Cell ◽  
Future Research ◽  
Barr Virus ◽  
Lymphoid Malignancies ◽  
Ebv Infection ◽  
Immune Correlates ◽  
Epstein Barr ◽  
Realistic Goal

The complex interplay between host and EBV has made it difficult to elaborate useful vaccines protecting against EBV diseases. It is encouraging to see that EBV vaccine programs have started to incorporate different arms of the immune system. An array of argument calls for a realistic goal for vaccine strategies which should be preventing EBV diseases, rather than EBV infection. EBV is the primary cause of infectious mononucleosis and is associated with epithelial cell carcinomas, as well as lymphoid malignancies. Parallel to this need, one could propose priorities for future research: (i) identification of surrogate predictive markers for the development of EBV diseases (ii) determination of immune correlates of protection in animal models and humans.

scholarly journals Hippo signaling effectors YAP and TAZ induce Epstein-Barr Virus (EBV) lytic reactivation through TEADs in epithelial cells

2021 ◽  
Vol 17 (8) ◽  
pp. e1009783
Author(s):  
Nicholas Van Sciver ◽  
Makoto Ohashi ◽  
Nicholas P. Pauly ◽  
Jillian A. Bristol ◽  
Scott E. Nelson ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Hippo Signaling ◽  
Oral Keratinocytes ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lytic Reactivation ◽  
Epstein Barr

The Epstein-Barr virus (EBV) human herpesvirus is associated with B-cell and epithelial-cell malignancies, and both the latent and lytic forms of viral infection contribute to the development of EBV-associated tumors. Here we show that the Hippo signaling effectors, YAP and TAZ, promote lytic EBV reactivation in epithelial cells. The transcriptional co-activators YAP/TAZ (which are inhibited by Hippo signaling) interact with DNA-binding proteins, particularly TEADs, to induce transcription. We demonstrate that depletion of either YAP or TAZ inhibits the ability of phorbol ester (TPA) treatment, cellular differentiation or the EBV BRLF1 immediate-early (IE) protein to induce lytic EBV reactivation in oral keratinocytes, and show that over-expression of constitutively active forms of YAP and TAZ reactivate lytic EBV infection in conjunction with TEAD family members. Mechanistically, we find that YAP and TAZ interact with, and activate, the EBV BZLF1 immediate-early promoter. Furthermore, we demonstrate that YAP, TAZ, and TEAD family members are expressed at much higher levels in epithelial cell lines in comparison to B-cell lines, and find that EBV infection of oral keratinocytes increases the level of activated (dephosphorylated) YAP and TAZ. Finally, we have discovered that lysophosphatidic acid (LPA), a known YAP/TAZ activator that plays an important role in inflammation, induces EBV lytic reactivation in epithelial cells through a YAP/TAZ dependent mechanism. Together these results establish that YAP/TAZ are powerful inducers of the lytic form of EBV infection and suggest that the ability of EBV to enter latency in B cells at least partially reflects the extremely low levels of YAP/TAZ and TEADs in this cell type.

scholarly journals Epstein-Barr-Virus-Encoded LMP2A Induces Primary Epithelial Cell Migration and Invasion: Possible Role in Nasopharyngeal Carcinoma Metastasis

2005 ◽  
Vol 79 (24) ◽  
pp. 15430-15442 ◽  
Author(s):  
Dirk M. Pegtel ◽  
Aravind Subramanian ◽  
Tzung-Shiahn Sheen ◽  
Ching-Hwa Tsai ◽  
Todd R. Golub ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Cellular Migration ◽  
Migration And Invasion ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epithelial Cell Migration ◽  
Epstein Barr

ABSTRACT Nonkeratinizing nasopharyngeal carcinomas (NPC) are >95% associated with the expression of the Epstein-Barr virus (EBV) LMP2A latent protein. However, the role of EBV, in particular, LMP2A, in tumor progression is not well understood. Using Affymetrix chips and a pattern-matching computational technique (neighborhood analysis), we show that the level of LMP2A expression in NPC biopsy samples correlates with that of a cellular protein, integrin-alpha-6 (ITGα6), that is associated with cellular migration in vitro and metastasis in vivo. We have recently developed a primary epithelial model from tonsil tissue to study EBV infection in epithelial cells. Here we report that LMP2A expression in primary tonsil epithelial cells causes them to become migratory and invasive, that ITGα6 RNA levels are up-regulated in epithelial cells expressing LMP2, and that ITGα6 protein levels are increased in the migrating cells. Blocking antibodies against ITGα6 abrogated LMP2-induced invasion through Matrigel by primary epithelial cells. Our results provide a link between LMP2A expression, ITGα6 expression, epithelial cell migration, and NPC metastasis and suggest that EBV infection may contribute to the high incidence of metastasis in NPC progression.

scholarly journals Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Mark R. Eichelberg ◽  
Rene Welch ◽  
J. Tod Guidry ◽  
Ahmed Ali ◽  
Makoto Ohashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Oral Epithelial

ABSTRACT Epstein-Barr virus (EBV) is a human herpesvirus that is associated with lymphomas as well as nasopharyngeal and gastric carcinomas. Although carcinomas account for almost 90% of EBV-associated cancers, progress in examining EBV’s role in their pathogenesis has been limited by difficulty in establishing latent infection in nontransformed epithelial cells. Recently, EBV infection of human telomerase reverse transcriptase (hTERT)-immortalized normal oral keratinocytes (NOKs) has emerged as a model that recapitulates aspects of EBV infection in vivo, such as differentiation-associated viral replication. Using uninfected NOKs and NOKs infected with the Akata strain of EBV (NOKs-Akata), we examined changes in gene expression due to EBV infection and differentiation. Latent EBV infection produced very few significant gene expression changes in undifferentiated NOKs but significantly reduced the extent of differentiation-induced gene expression changes. Gene set enrichment analysis revealed that differentiation-induced downregulation of the cell cycle and metabolism pathways was markedly attenuated in NOKs-Akata relative to that in uninfected NOKs. We also observed that pathways induced by differentiation were less upregulated in NOKs-Akata. We observed decreased differentiation markers and increased suprabasal MCM7 expression in NOKs-Akata versus NOKs when both were grown in raft cultures, consistent with our transcriptome sequencing (RNA-seq) results. These effects were also observed in NOKs infected with a replication-defective EBV mutant (AkataΔRZ), implicating mechanisms other than lytic-gene-induced host shutoff. Our results help to define the mechanisms by which EBV infection alters keratinocyte differentiation and provide a basis for understanding the role of EBV in epithelial cancers. IMPORTANCE Latent infection by Epstein-Barr virus (EBV) is an early event in the development of EBV-associated carcinomas. In oral epithelial tissues, EBV establishes a lytic infection of differentiated epithelial cells to facilitate the spread of the virus to new hosts. Because of limitations in existing model systems, the effects of latent EBV infection on undifferentiated and differentiating epithelial cells are poorly understood. Here, we characterize latent infection of an hTERT-immortalized oral epithelial cell line (NOKs). We find that although EBV expresses a latency pattern similar to that seen in EBV-associated carcinomas, infection of undifferentiated NOKs results in differential expression of a small number of host genes. In differentiating NOKs, however, EBV has a more substantial effect, reducing the extent of differentiation and delaying the exit from the cell cycle. This effect may synergize with preexisting cellular abnormalities to prevent exit from the cell cycle, representing a critical step in the development of cancer.

ASSOCIATION OF EPSTEIN-BARR VIRUS WITH LEIOMYOSARCOMAS IN YOUNG PEOPLE WITH AIDS

PEDIATRICS ◽  
1996 ◽  
Vol 98 (2) ◽  
pp. 347-347
Author(s):  
Maritza Navarro ◽  
I. Celine Hanson
Keyword(s):  
Smooth Muscle ◽  
Immune System ◽  
Epstein Barr Virus ◽  
Receptor Expression ◽  
Barr Virus ◽  
Ebv Infection ◽  
Smooth Muscle Tumors ◽  
Epstein Barr ◽  
Negative Controls ◽  
Hiv Negative

EBV was found in all smooth muscle tumors from the six HIV-infected cases, but not in smooth muscle tumors from HIV-negative controls. All tumors studied stained for CD21 (EBV receptor), but levels were higher on tumor cells from HIV-infected cases than controls. This suggests that perturbation of the immune system (as in AIDS) may increase the production of the EBV receptor and/or that EBV infection itself causes increased receptor expression. It is postulated that EBV may contribute to smooth muscle tumorigenesis in HIV infection and potentially in other immunosuppressed states.

scholarly journals Molecular Evidence for Rhesus Lymphocryptovirus Infection of Epithelial Cells in Immunosuppressed Rhesus Macaques

2004 ◽  
Vol 78 (7) ◽  
pp. 3455-3461 ◽  
Author(s):  
Jeffery L. Kutok ◽  
Sherry Klumpp ◽  
Meredith Simon ◽  
John J. MacKey ◽  
Vuong Nguyen ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
B Cell ◽  
Rhesus Macaques ◽  
Molecular Evidence ◽  
Cell Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with epithelial cell and B-cell malignancies. EBV infection of B lymphocytes is essential for acute and persistent EBV infection in humans; however, the role of epithelial cell infection in the normal EBV life cycle remains controversial. The rhesus lymphocryptovirus (LCV) is an EBV-related herpesvirus that naturally infects rhesus macaques and can be used experimentally to model persistent B-cell infection and B-cell lymphomagenesis. We now show that the rhesus LCV can infect epithelial cells in immunosuppressed rhesus macaques and can induce epithelial cell lesions resembling oral hairy leukoplakia in AIDS patients. Electron microscopy, immunohistochemistry, and DNA-RNA in situ hybridization were used to identify the presence of a lytic rhesus LCV infection in these proliferative, hyperkeratotic, or parakeratotic epithelial cell lesions. These studies demonstrate that the rhesus LCV has tropism for epithelial cells, in addition to B cells, and is a relevant animal model system for studying the role of epithelial cell infection in EBV pathogenesis.

scholarly journals Overexpression of PD-1 on Peripheral Blood Lymphocytes in Patients with Idiopathic Pulmonary Arterial Hypertension and Its Association with High Viral Loads of Epstein-Barr Virus and Poor Clinical Parameters

2020 ◽  
Vol 9 (6) ◽  
pp. 1966 ◽  
Author(s):  
Michał Tomaszewski ◽  
Ewelina Grywalska ◽  
Andrzej Tomaszewski ◽  
Piotr Błaszczak ◽  
Marcin Kurzyna ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Epstein Barr Virus ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Barr Virus ◽  
Ebv Infection ◽  
Pulmonary Arterial ◽  
Epstein Barr

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe disease with the elevated blood pressure in the pulmonary arteries without a known trigger of vascular remodelling. It leads to the right heart failure with reduced survival. Changes in the immunological landscape of the lungs and the periphery are common in IPAH patients, suggesting an immune system dysfunction. A cohort of 25 IPAH patients was enrolled in our study to investigate a link between the patient’s clinical status, immune parameters of the blood, and the Epstein–Barr virus (EBV) infection. We found significant alterations of the patients’ peripheral blood parameters. Therein, T lymphocytes and NK cell counts were decreased in the IPAH patients’ blood, while the proportion of regulatory T cells was increased. Additionally, levels of proinflammatory cytokines interleukin-6 (IL-6), IL-2, and interferon-gamma (IFN-γ) were elevated. We identified a weak correlation between EBV loads and IPAH patients’ clinical state (r = 0.54) and between EBV loads and overexpression of PD-1 on helper T cells (r = 0.56). We speculate that a significant dysregulation of the immune system homeostasis observed in IPAH patients may contribute to increased susceptibility of those patients to EBV infection, yet further longitudinal studies are required to characterize this relation in detail.

scholarly journals Epstein-Barr Virus Infection in Ex Vivo Tonsil Epithelial Cell Cultures of Asymptomatic Carriers

2004 ◽  
Vol 78 (22) ◽  
pp. 12613-12624 ◽  
Author(s):  
Dirk M. Pegtel ◽  
Jaap Middeldorp ◽  
David A. Thorley-Lawson
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Cell Cultures ◽  
Epstein Barr Virus ◽  
Ex Vivo ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is found frequently in certain epithelial pathologies, such as nasopharyngeal carcinoma and oral hairy leukoplakia, indicating that the virus can infect epithelial cells in vivo. Recent studies of cell lines imply that epithelial cells may also play a role in persistent EBV infection in vivo. In this report, we show the establishment and characterization of an ex vivo culture model of tonsil epithelial cells, a likely site for EBV infection in vivo. Primary epithelial-cell cultures, generated from tonsil explants, contained a heterogeneous mixture of cells with an ongoing process of differentiation. Keratin expression profiles were consistent with the presence of cells from both surface and crypt epithelia. A small subset of cells could be latently infected by coculture with EBV-releasing cell lines, but not with cell-free virus. We also detected viral-DNA, -mRNA, and -protein expression in cultures from EBV-positive tonsil donors prior to in vitro infection. We conclude that these cells were either already infected at the time of explantation or soon after through cell-to-cell contact with B cells replicating EBV in the explant. Taken together, these findings suggest that the tonsil epithelium of asymptomatic virus carriers is able to sustain EBV infection in vivo. This provides an explanation for the presence of EBV in naso- and oropharyngeal pathologies and is consistent with epithelial cells playing a role in the egress of EBV during persistent infection.

scholarly journals Roles of Epstein–Barr virus glycoproteins gp350 and gp25 in the infection of human epithelial cells

2001 ◽  
Vol 82 (10) ◽  
pp. 2373-2383 ◽  
Author(s):  
Seiji Maruo ◽  
Lixin Yang ◽  
Kenzo Takada
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Fluorescent Protein ◽  
The Other ◽  
Soluble Form ◽  
Epithelial Cell Line ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Epstein–Barr virus (EBV) is associated with various epithelial malignancies such as nasopharyngeal carcinoma and gastric carcinoma, and causes oral hairy leukoplakia, a productive EBV infection of the differentiated epithelium of the tongue. However, it is not clear by what mechanism EBV infects epithelial cells. We generated a recombinant EBV that expresses enhanced green fluorescent protein in order to monitor EBV entrance into epithelial cells quickly and quantitatively. Using this monitoring system, we examined the roles of gp350 and gp25 in EBV infection of epithelial cells by utilizing soluble forms of the gp350 and gp25 proteins. EBV infection of three of four examined epithelial cell lines, 293, NU-GC-3 and Lovo, was almost completely blocked by pretreatment of cells with a soluble form of gp350 (designated gp350Ig), and this blockage was dependent on the CD21-binding region of gp350. On the other hand, infection of the other epithelial cell line, AGS, was not inhibited at all by pretreatment with gp350Ig. Moreover, we found that a soluble form of gp25 (designated gp25Ig) preferentially bound to epithelial cells rather than B cells, and pretreatment of cells with gp25Ig substantially blocked EBV infection of some epithelial cells. These results indicate the existence of two distinct pathways in EBV infection of epithelial cells, a gp350-dependent pathway and a gp350-independent pathway, and that gp25 can play a role in the infection of some epithelial cells.

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