Epstein–Barr virus, latitude and multiple sclerosis

Several lines of evidence support a role for Epstein–Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02–1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

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Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis

Medical Hypotheses ◽

10.1016/j.mehy.2007.04.030 ◽

2008 ◽

Vol 70 (1) ◽

pp. 66-69 ◽

Cited By ~ 43

Author(s):

Trygve Holmøy

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Vitamin D ◽

Immune Response ◽

Synergistic Effect ◽

Epstein Barr Virus ◽

Vitamin D Status ◽

Barr Virus ◽

Epstein Barr

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Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Journal of Innate Immunity ◽

10.1159/000479749 ◽

2017 ◽

Vol 9 (6) ◽

pp. 574-586 ◽

Cited By ~ 33

Author(s):

Yuanjun Lu ◽

Zailong Qin ◽

Jia Wang ◽

Xiang Zheng ◽

Jianhong Lu ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Epstein Barr Virus ◽

Type I ◽

Receptor Signaling ◽

Viral Pathogen ◽

Infection Period ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

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Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors

10.1101/19007450 ◽

2019 ◽

Cited By ~ 1

Author(s):

Benjamin M Jacobs ◽

Gavin Giovannoni ◽

Jack Cuzick ◽

Ruth Dobson

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Epstein Barr Virus ◽

Meta Analysis ◽

Clinically Isolated Syndrome ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

Hla Genotype ◽

Additive Scale

AbstractBackgroundEBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.ObjectiveTo examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.MethodsPubmed was searched using the terms “multiple sclerosis” AND “Epstein Barr virus”, “multiple sclerosis” AND EBV, “clinically isolated syndrome” AND “Epstein Barr virus” and “clinically isolated syndrome” AND EBV. All abstracts were reviewed for possible inclusion.Results262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10−4; RERI 3.84, p<5×10−3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.ConclusionsEBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

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Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis

10.21203/rs.3.rs-792416/v1 ◽

2021 ◽

Author(s):

Asma Hassani ◽

Narendran Reguraman ◽

Safa Shehab ◽

Gulfaraz Khan

Keyword(s):

Multiple Sclerosis ◽

Epstein Barr Virus ◽

Rabbit Model ◽

Nerve Fibers ◽

Cns Infection ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

Cellular Aggregates ◽

The Brain

Abstract Background: Epstein-Barr virus (EBV) is a common herpesvirus associated with malignant and non-malignant conditions. An accumulating body of evidence supports a role for EBV in the pathogenesis of multiple sclerosis (MS), a demyelinative disease of the CNS. However, little is known about the details of the link between EBV and MS. One obstacle which has hindered research in this area has been the lack of a suitable animal model recapitulating natural infection in humans. We have recently shown that healthy rabbits are susceptible to EBV infection, and viral persistence in these animals mimics latent infection in humans. Methods: We used the rabbit model to investigate if peripheral EBV infection can lead to infection of the CNS and its potential consequences. We injected EBV intravenously in one group of animals, and PBS in another, with and without immunosuppression. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques. Results: Our investigations uncovered important findings that could not be previously addressed. We showed that primary peripheral EBV infection can lead to the virus traversing the CNS. Cell associated, but not free virus in the plasma, correlated with CNS infection. The infected cells within the brain were found to be B-lymphocytes. Most notably, animals injected with EBV, but not PBS, developed inflammatory cellular aggregates in the CNS. The incidence of these aggregates increased in the immunosuppressed animals. The cellular aggregates contained compact clusters of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes, but not myelinated nerve fibers. Moreover, studying EBV infection over a span of 28 days, revealed that the peak point for viral load in the periphery and CNS coincides with increased occurrence of cellular aggregates in the brain. Finally, peripheral EBV infection triggered temporal changes in the expression of latent viral transcripts and cytokines in the brain. Conclusion: The present study provides the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and highlights a unique model to dissect viral mechanisms contributing to the development of MS.

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An Absence of Epstein–Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination

Vaccines ◽

10.3390/vaccines8030487 ◽

2020 ◽

Vol 8 (3) ◽

pp. 487

Author(s):

Peter A. C. Maple ◽

Bruno Gran ◽

Radu Tanasescu ◽

David I. Pritchard ◽

Cris S. Constantinescu

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Epstein Barr Virus ◽

Nuclear Antigen ◽

Virus Reactivation ◽

Serum Samples ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Reactivation ◽

Epstein Barr

Background: Epstein–Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). Helminth infection can downregulate antiviral immune responses, potentially protecting against MS, but with a theoretical risk for reactivating latent EBV infection. Objective: To investigate parameters of EBV infection and their relationship with disease activity in people with MS (PwMS) therapeutically vaccinated with Necator americanus (hookworm). Methods: Sequential serum samples from 51 PwMS; 26 therapeutically infected (25 larvae) with N. americanus and 25 controls were tested for EBV virus capsid antigen (VCA) IgG and IgM, EBV nuclear antigen-1 (EBNA-1) IgG, and EBV early antigen (EA) IgG. Disease activity was assessed by periodic MRI. Significance was set at p < 0.05. Results: All PwMS were EBV VCA IgG and EBNA-1 IgG positive, and 35.2% were EBV EA IgG positive. EBV antibody levels were generally stable, and EBV reactivation in PwMS was not demonstrated by significant increases in IgG titre over 12 months. Disease activity was most frequent in PwMS possessing high levels of EBV VCA IgG (>600 units/mL) or EBNA-1 IgG (>150 units/mL); however, there was no association with hookworm treatment. Interpretation: Therapeutic hookworm vaccination was not associated with EBV reactivation. Multiple sclerosis disease activity was associated with high levels of EBV VCA IgG or EBNA-1 IgG.

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Epstein-Barr virus and multiple sclerosis: Cellular immune response and cross-reactivity

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2010.08.009 ◽

2010 ◽

Vol 229 (1-2) ◽

pp. 238-242 ◽

Cited By ~ 18

Author(s):

J. William Lindsey ◽

Landon M. Hatfield

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Cellular Immune Response ◽

Epstein Barr Virus ◽

Cross Reactivity ◽

Barr Virus ◽

Epstein Barr ◽

Cellular Immune

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

Genes and Immunity ◽

10.1038/s41435-019-0089-5 ◽

2019 ◽

Vol 21 (2) ◽

pp. 91-99 ◽

Cited By ~ 1

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.

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Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination

Multiple Sclerosis Journal ◽

10.1177/1352458515595876 ◽

2015 ◽

Vol 22 (3) ◽

pp. 385-388 ◽

Cited By ~ 23

Author(s):

Naila Makhani ◽

Brenda Banwell ◽

Raymond Tellier ◽

Carmen Yea ◽

Suzanne McGovern ◽

...

Keyword(s):

Multiple Sclerosis ◽

Epstein Barr Virus ◽

Protective Factor ◽

Cmv Infection ◽

Prognostic Information ◽

Varicella Zoster ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

Simplex Virus

Epstein–Barr virus (EBV) infection is associated with increased multiple sclerosis (MS) risk. Recently, cytomegalovirus (CMV) infection has been proposed as a protective factor against MS development. We determined EBV, herpes simplex virus, varicella-zoster virus and CMV seroprevalence in 247 prospectively followed children with acquired demyelinating syndromes (ADS). Remote EBV infection was more common in children with MS than those with monophasic ADS while CMV infection was more common in children with monophasic ADS. Children displaying evidence of remote EBV without CMV infection were at highest risk of subsequent MS diagnosis. Viral infection repertoire detected at ADS provides important prognostic information.

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Differential Methylation of Epstein-Barr Virus Latency Promoters Facilitates Viral Persistence in Healthy Seropositive Individuals

Journal of Virology ◽

10.1128/jvi.73.12.9959-9968.1999 ◽

1999 ◽

Vol 73 (12) ◽

pp. 9959-9968 ◽

Cited By ~ 49

Author(s):

Emily J. Paulson ◽

Samuel H. Speck

Keyword(s):

Gene Expression ◽

Immune Response ◽

Viral Genome ◽

Epstein Barr Virus ◽

Critical Role ◽

Viral Gene ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) establishes a life-long infection in humans, with distinct viral latency programs predominating during acute and chronic phases of infection. Only a subset of the EBV latency-associated antigens present during the acute phase of EBV infection are expressed in the latently infected memory B cells that serve as the long-term EBV reservoir. Since the EBV immortalization program elicits a potent cellular immune response, downregulation of viral gene expression in the long-term latency reservoir is likely to facilitate evasion of the immune response and persistence of EBV in the immunocompetent host. Tissue culture and tumor models of restricted EBV latency have consistently demonstrated a critical role for methylation of the viral genome in maintaining the restricted pattern of latency-associated gene expression. Here we extend these observations to demonstrate that the EBV genomes in the memory B-cell reservoir are also heavily and discretely methylated. This analysis reveals that methylation of the viral genome is a normal aspect of EBV infection in healthy immunocompetent individuals and is not restricted to the development of EBV-associated tumors. In addition, the pattern of methylation very likely accounts for the observed inhibition of the EBV immortalization program and the establishment and maintenance of a restricted latency program. Thus, EBV appears to be the first example of a parasite that usurps the host cell-directed methylation system to regulate pathogen gene expression and thereby establish a chronic infection.

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