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Epstein–Barr Virus Infection and Associated Diseases

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 43126

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Prof. Dr. Asuka Nanbo

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National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan
Interests: virology (EBV, Ebola virus); host-virus interaction; exosome; microRNA; viral entry; viral particle formation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Epstein-Barr virus (EBV), a ubiquitous human gammaherpesvirus, infects a majority of the population worldwide (~95%) and establishes a persistent, lifelong, mostly asymptomatic infection in them. EBV infection is also associated with various lymphoid and epithelial malignancies such as Burkitt’s lymphoma, Hodgkin’s disease, gastric carcinoma, and nasopharyngeal carcinoma, as well as post-transplant lymphoproliferative disorders.

Accumulating evidence implies that a variety of viral proteins, which mimic host growth factor receptors, transcription factors, and anti-apoptotic factors, contribute to EBV-associated cancers. Moreover, recent observations have demonstrated the important roles of viral non-coding RNAs, extracellular vesicles derived from infected cells, and viral genomic variation. However, we still do not understand why EBV causes cancer in only a small percentage of the population.

The aim of this Special Issue is to give insights into the mechanism of development of EBV-associated cancers. For this purpose, I invite you to submit research articles, review articles, and short communications related to EBV-associated cancers on topics such as virus–host interactions, noncoding RNAs, signaling pathways, extracellular vesicles, genome variability, immune evasion, epigenomics, and therapeutics. As a Guest Editor of this Special Issue, I look forward to reviewing your submissions and, together, defining the present state of the science.

Prof. Dr. Asuka Nanbo
Guest Editor

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Keywords

Virus–cell intercations
Noncoding RNAs
Signaling pathways
Extracellular vesicles
Genome variability
Immune evasion
Epigenomics
Therapeutics

Published Papers (12 papers)

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Editorial

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2 pages, 161 KiB

Open AccessEditorial

Special Issue: Epstein–Barr–Virus–Associated Cancers

by Asuka Nanbo

Microorganisms 2021, 9(2), 241; https://doi.org/10.3390/microorganisms9020241 - 25 Jan 2021

Viewed by 1233

Abstract

Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, infects a majority of the population worldwide (~95%) [...] Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

Research

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15 pages, 3590 KiB

Open AccessArticle

Exosomes of Epstein-Barr Virus-Associated Gastric Carcinoma Suppress Dendritic Cell Maturation

by Munetoshi Hinata, Akiko Kunita, Hiroyuki Abe, Yasuyuki Morishita, Kei Sakuma, Hiroharu Yamashita, Yasuyuki Seto, Tetsuo Ushiku and Masashi Fukayama

Microorganisms 2020, 8(11), 1776; https://doi.org/10.3390/microorganisms8111776 - 12 Nov 2020

Cited by 24 | Viewed by 2641

Abstract

The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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9 pages, 1146 KiB

Open AccessArticle

Application of Biopsy Samples Used for Helicobacter pylori Urease Test to Predict Epstein–Barr Virus-Associated Cancer

by Andy Visi Kartika, Hisashi Iizasa, Dan Ding, Yuichi Kanehiro, Yoshitsugu Tajima, Shunsuke Kaji, Hideo Yanai and Hironori Yoshiyama

Microorganisms 2020, 8(6), 923; https://doi.org/10.3390/microorganisms8060923 - 18 Jun 2020

Cited by 8 | Viewed by 2497

Abstract

Persistent gastric mucosal damage caused by Helicobacter pylori infection is a major risk factor for gastric cancer (GC). The Epstein–Barr virus (EBV) is also associated with GC. Most patients with EBV-associated GC are infected with H. pylori in East Asia. However, very few reports have described where and when both H. pylori and EBV infect the gastric mucosa. To clarify this, old biopsy samples used for the rapid urease test (RUT) were applied to count EBV genomic DNA (gDNA) copies using DNA probe quantitative polymerase chain reaction. DNA extracted from the gastric biopsy samples of 58 patients with atrophic gastritis was used to analyze the correlation between the degree of atrophic gastritis and the copy number of EBV gDNA. EBV was detected in 44 cases (75.9%), with viral copy numbers ranging from 12.6 to 4754.6. A significant correlation was found between patients with more than 900 copies of EBV gDNA and those with a more severe grade of atrophic gastritis (p = 0.041). This study shows that EBV can be detected in RUT samples in a manner that reduces patient burden. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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12 pages, 2784 KiB

Open AccessArticle

Epstein-Barr Virus Exploits the Secretory Pathway to Release Virions

by Asuka Nanbo

Microorganisms 2020, 8(5), 729; https://doi.org/10.3390/microorganisms8050729 - 13 May 2020

Cited by 7 | Viewed by 2673

Abstract

Herpesvirus egress mechanisms are strongly associated with intracellular compartment remodeling processes. Previously, we and other groups have described that intracellular compartments derived from the Golgi apparatus are the maturation sites of Epstein-Barr virus (EBV) virions. However, the mechanism by which these virions are released from the host cell to the extracellular milieu is poorly understood. Here, I adapted two independent induction systems of the EBV lytic cycle in vitro, in the context of Rab GTPase silencing, to characterize the EBV release pathway. Immunofluorescence staining revealed that p350/220, the major EBV glycoprotein, partially co-localized with three Rab GTPases: Rab8a, Rab10, and Rab11a. Furthermore, the knockdown of these Rab GTPases promoted the intracellular accumulation of viral structural proteins by inhibiting its distribution to the plasma membrane. Finally, the knockdown of the Rab8a, Rab10, and Rab11a proteins suppressed the release of EBV infectious virions. Taken together, these findings support the hypothesis that mature EBV virions are released from infected cells to the extracellular milieu via the secretory pathway, as well as providing new insights into the EBV life cycle. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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17 pages, 7687 KiB

Open AccessArticle

Epstein–Barr Virus Infection of Oral Squamous Cells

by Chukkris Heawchaiyaphum, Hisashi Iizasa, Tipaya Ekalaksananan, Ati Burassakarn, Tohru Kiyono, Yuichi Kanehiro, Hironori Yoshiyama and Chamsai Pientong

Microorganisms 2020, 8(3), 419; https://doi.org/10.3390/microorganisms8030419 - 16 Mar 2020

Cited by 19 | Viewed by 7125

Abstract

The Epstein–Barr virus (EBV) is a human herpesvirus associated with various cancers. The number of reports that describe infection of EBV in oral squamous carcinoma cells is increasing. However, there is no available in vitro model to study the possible role of EBV in the development of oral squamous cell carcinoma. Herein, we report establishment of a latent EBV infection of well-differentiated HSC1 cells and poorly differentiated SCC25 cells. Viral copy numbers per cell in EBV-infected HSC1 and SCC25 cells are 2 and 5, respectively. Although the EBV copy number was small, spontaneous viral replication was observed in EBV-infected HSC1 cells. Contrarily, infectious viral production was not observed in EBV-infected SCC25 cells, despite containing larger number of EBV genomes. Chemical activation of cells induced expression of viral lytic BZLF1 gene in EBV-infected HSC1 cells, but not in EBV-infected SCC25 cells. EBV infection activated proliferation and migration of HSC1 cells. However, EBV-infection activated migration but not proliferation in SCC25 cells. In conclusion, EBV can infect squamous cells and establish latent infection, but promotion of cell proliferation and of lytic EBV replication may vary depending on stages of cell differentiation. Our model can be used to study the role of EBV in the development of EBV-associated oral squamous cell carcinoma. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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17 pages, 1414 KiB

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Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer

by Jae Hee Yoon, Kyoungmi Min and Suk Kyeong Lee

Microorganisms 2020, 8(2), 258; https://doi.org/10.3390/microorganisms8020258 - 15 Feb 2020

Cited by 15 | Viewed by 2775

Abstract

Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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14 pages, 2978 KiB

Open AccessArticle

Epstein-Barr Virus BBRF2 Is Required for Maximum Infectivity

by H. M. Abdullah Al Masud, Yusuke Yanagi, Takahiro Watanabe, Yoshitaka Sato, Hiroshi Kimura and Takayuki Murata

Microorganisms 2019, 7(12), 705; https://doi.org/10.3390/microorganisms7120705 - 16 Dec 2019

Cited by 9 | Viewed by 3423

Abstract

Epstein-Barr virus (EBV) is a member of the gammaherpesvirinae, which causes infectious mononucleosis and several types of cancer. BBRF2 is an uncharacterized gene of EBV and is expressed during the lytic phase. To evaluate its function, BBRF2-knockout EBV was prepared using bacterial artificial chromosome (BAC) technology and the CRISPR/Cas9 system. Although viral gene expression, DNA synthesis, and progeny secretion were not affected, the infectivity of progeny viruses was significantly reduced by the disruption of BBRF2. When expressed alone, BBRF2 protein localized to the nucleus and cytoplasm, while the coexpression of an interacting partner, BSRF1, resulted in its relocalization to the cytoplasm. Interestingly, the coexpression of BBRF2 protected BSRF1 from proteasome/ubiquitin-dependent degradation. Therefore, BBRF2, together with BSRF1, augments viral infectivity. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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9 pages, 2879 KiB

Open AccessArticle

Establishment of a Screening Method for Epstein-Barr Virus-Associated Gastric Carcinoma by Droplet Digital PCR

by Takuya Shuto, Jun Nishikawa, Kanami Shimokuri, Ayaka Yanagi, Tatsuya Takagi, Fumiya Takagi, Osamu Miura, Michihisa Iida, Hiroaki Nagano, Yoshihiro Takemoto, Eijiro Harada, Yutaka Suehiro, Takahiro Yamasaki, Takeshi Okamoto and Isao Sakaida

Microorganisms 2019, 7(12), 628; https://doi.org/10.3390/microorganisms7120628 - 29 Nov 2019

Cited by 11 | Viewed by 3175

Abstract

Background: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is classified as one of the molecular subtypes of gastric cancer. We used droplet digital polymerase chain reaction (ddPCR) to enable highly sensitive and quantitative detection of EBV. Methods: EBV-DNA load was calculated based on the copy number of the BamH1-W fragment of EBV by ddPCR, and the cut-off value of EBV-DNA load was set. We conducted both ddPCR and EBER1 ISH to examine whether their results coincided in 158 gastric cancer specimens of unknown EBV status. We prepared 26 biopsy specimens and 49 serum samples including EBVaGC and assayed them by ddPCR. Results: The median values of EBV-DNA load for EBVaGC and EBV-negative control were 17.0 and 0.00308, respectively. A cut-off value of 0.032 was determined for which the sensitivity was 1. Among the 158 gastric cancer specimens, 14 lesions were judged as EBV-positive by the 0.032 cut-off value determined by ddPCR. The results of ddPCR and EBER1 ISH were in complete agreement. Even when using a biopsy specimen as a sample for ddPCR, the EBV-DNA load of all EBVaGCs was larger than the cut-off value. Conclusions: We established a new method of diagnosing EBVaGC from tissue samples by ddPCR. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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Review

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15 pages, 1479 KiB

Open AccessReview

Epstein–Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity

by Keiko Nagata and Kazuhiko Hayashi

Microorganisms 2020, 8(12), 1875; https://doi.org/10.3390/microorganisms8121875 - 27 Nov 2020

Cited by 15 | Viewed by 4044

Abstract

Epstein–Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV reactivation and its relevance to autoimmune disease, focusing on Graves’ disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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19 pages, 689 KiB

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Epstein–Barr Virus: How Its Lytic Phase Contributes to Oncogenesis

by Quincy Rosemarie and Bill Sugden

Microorganisms 2020, 8(11), 1824; https://doi.org/10.3390/microorganisms8111824 - 19 Nov 2020

Cited by 62 | Viewed by 6754

Abstract

Epstein–Barr Virus (EBV) contributes to the development of lymphoid and epithelial malignancies. While EBV’s latent phase is more commonly associated with EBV-associated malignancies, there is increasing evidence that EBV’s lytic phase plays a role in EBV-mediated oncogenesis. The lytic phase contributes to oncogenesis primarily in two ways: (1) the production of infectious particles to infect more cells, and (2) the regulation of cellular oncogenic pathways, both cell autonomously and non-cell autonomously. The production of infectious particles requires the completion of the lytic phase. However, the regulation of cellular oncogenic pathways can be mediated by an incomplete (abortive) lytic phase, in which early lytic gene products contribute substantially, whereas late lytic products are largely dispensable. In this review, we discuss the evidence of EBV’s lytic phase contributing to oncogenesis and the role it plays in tumor formation and progression, as well as summarize known mechanisms by which EBV lytic products regulate oncogenic pathways. Understanding the contribution of EBV’s lytic phase to oncogenesis will help design ways to target it to treat EBV-associated malignancies. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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Other

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11 pages, 18406 KiB

Open AccessBrief Report

Variable Expression of Notch1 and Pax5 in Classical Hodgkin Lymphoma and Infection with Epstein–Barr in Pediatric Patients

by Icela Palma-Lara, Ana Elena Sánchez-Aldana, Elva Jiménez-Hernández, Octavio Martínez-Villegas, Juan Carlos Núñez-Enríquez, Juan Manuel Mejía-Aranguré, Sara A. Ochoa, Juan Xicohtencatl-Cortes, Ariadnna Cruz-Córdova, Sergio Zavala-Vega, Mariana García-Jiménez, Alejandra Contreras-Ramos, José Refugio Torres-Nava, Guillermo Mora-Ramiro and José Arellano-Galindo

Microorganisms 2020, 8(6), 958; https://doi.org/10.3390/microorganisms8060958 - 26 Jun 2020

Cited by 2 | Viewed by 2961

Abstract

NOTCH1 and PAX5 participate in the proliferation and differentiation of B and T lymphocytes. Their expression can be modified by activation of NOTCH1, induced by the Epstein–Barr (EBV) viral proteins identified as LMP1 and LMP2. To identify whether PAX5, NOTCH1, and EBV latency genes participate in the oncogenic process of pediatric patients with classical Hodgkin lymphoma (cHL), the present study aimed to identify the variable expression of NOTCH1 among disease subtypes and to assess its effect on PAX5 expression. A total of 41 paraffin-embedded tissues from Mexican pediatric patients with cHL were analyzed. The expression of CD30, CD20, NOTCH1, PAX5, and LMP1 was evaluated by immunohistochemistry and immunofluorescence. EBV detection was performed by in situ hybridization. Out of all cases, 78% (32/41) of the cHL cases were EBV positive. NOTCH1 expression was detected in 78.1% (25/32) of EBV-positive cases, nodular sclerosis being the most frequent subtype (11/25, 44%). In cases where the expression of both genes was identified, double immunofluorescence assays were conducted, finding no colocalization. We found that Reed–Sternberg cells had aberrant expression compared to their cells of origin (B lymphocytes) due to the molecular mechanisms involved in the loss of expression of PAX5 and that the identification of NOTCH1 could be considered as a candidate diagnostic/prognostic marker and a therapeutic target in pediatric cHL. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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12 pages, 20197 KiB

Open AccessBrief Report

Overexpression of Semaphorin 3A Is a Marker Associated with Poor Prognosis in Patients with Nasopharyngeal Carcinoma

by Tomoko Imoto, Satoru Kondo, Naohiro Wakisaka, Pham Tahnh Hai, Noriko Seishima, Makoto Kano, Takayoshi Ueno, Harue Mizokami, Yosuke Nakanishi, Miyako Hatano, Kazuhira Endo, Hisashi Sugimoto, Makiko Moriyama-Kita and Tomokazu Yoshizaki

Microorganisms 2020, 8(3), 423; https://doi.org/10.3390/microorganisms8030423 - 17 Mar 2020

Cited by 5 | Viewed by 2490

Abstract

Semaphorins were discovered as guidance signals that mediate neural development. Recent studies suggest that semaphorin 3A (Sema3A), a member of the semaphorin family, is involved in the development of several cancers. This study aimed to analyze the association of Sema3A with the clinical features of nasopharyngeal carcinoma (NPC), an Epstein–Barr virus-associated carcinoma, and the Epstein–Barr virus primary oncogene latent membrane protein 1 (LMP1). The expression of Sema3A and LMP1 was immunohistochemically examined in the 35 NPC specimens. The mean expression scores for Sema3A and LMP1 were 20.8% ± 14.5% and 13.9% ± 14.8%, respectively. The expression of Sema3A significantly correlated with that of LMP1 (r = 0.41, p = 0.014). In addition, the Sema3A high cohort showed significantly poorer prognosis than the Sema3A low cohort. Sema3A expression was higher in the LMP1-positive KH-1 and KR-4 cell lines compared to the LMP1-negative HeLa cells. Overexpression of LMP1 in the LMP1-negative AdAH cell line upregulated Sema3A expression, both at the transcriptional and translational level. Finally, Sema3A expression was associated with poor prognosis in patients with NPC. Our data suggest that LMP1 induces the expression of Sema3A, which may promote tumor progression in NPC. Full article

(This article belongs to the Special Issue Epstein–Barr Virus Infection and Associated Diseases)

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