Tree Shrew Is a Suitable Animal Model for the Study of Epstein Barr Virus

Epstein-Barr virus (EBV) is a human herpesvirus that latently infects approximately 95% of adults and is associated with a spectrum of human diseases including Infectious Mononucleosis and a variety of malignancies. However, understanding the pathogenesis, vaccines and antiviral drugs for EBV-associated disease has been hampered by the lack of suitable animal models. Tree shrew is a novel laboratory animal with a close phylogenetic relationship to primates, which is a critical advantage for many animal models for human disease, especially viral infections. Herein, we first identified the key residues in the CR2 receptor that bind the gp350 protein and facilitate viral entry. We found that tree shrew shares 100% sequence identity with humans in these residues, which is much higher than rabbits (50%) and rats (25%). In vitro analysis showed that B lymphocytes of tree shrews are susceptible to EBV infection and replication, as well as EBV-enhanced cell proliferation. Moreover, results of in vivo experiments show that EBV infection in tree shrews resembles EBV infection in humans. The infected animals exhibited transient fever and loss of weight accompanied by neutropenia and high viremia levels during the acute phase of the viral infection. Thereafter, tree shrews acted as asymptomatic carriers of the virus in most cases that EBV-related protein could be detected in blood and tissues. However, a resurgence of EBV infection occurred at 49 dpi. Nanopore transcriptomic sequencing of peripheral blood in EBV-infected animals revealed the dynamic changes in biological processes occurring during EBV primary infection. Importantly, we find that neutrophil function was impaired in tree shrew model as well as human Infectious Mononucleosis datasets (GSE85599 and GSE45918). In addition, retrospective case reviews suggested that neutropenia may play an important role in EBV escaping host innate immune response, leading to long-term latent infection. Our findings demonstrated that tree shrew is a suitable animal model to evaluate the mechanisms of EBV infection, and for developing vaccines and therapeutic drugs against EBV.

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Encephalitis in Infectious Mononucleosis: Diagnostic Considerations

PEDIATRICS ◽

10.1542/peds.58.6.877 ◽

1976 ◽

Vol 58 (6) ◽

pp. 877-880

Author(s):

Beverly J. Lange ◽

Peter H. Berman ◽

Joseph Bender ◽

Werner Henle ◽

John F. Hewetson

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Nuclear Antigen ◽

Diffuse Component ◽

Early Antigen ◽

Barr Virus ◽

Ebv Infection ◽

Antibody Titers ◽

Epstein Barr ◽

Etiologic Diagnosis

Four atypical cases of presumed infectious mononucleosis (IM) encephalitis are presented. To establish an etiologic diagnosis, Paul-Bunnell-Davidsohn heterophil titers (PBD), antibody titers to the antigens of the Epstein-Barr virus (EBV), and oropharyngeal excretion of EBV were determined. Criteria for a primary EBV infection are (1) an antiviral capsid antigen titer of 1:160 or greater, (2) the presence of antibody to the diffuse component of the early antigen, (3) absence of antibody to the nuclear antigen, and (4) excretion of the virus from the oropharynx. Three of the four cases met these criteria; of the three, one did not have a positive heterophil titer. The fourth case turned out not to be IM; there was a positive PBD heterophil, but there was no evidence of primary EBV infection. Although the PBD heterophil is usually a reliable test to diagnosis IM, it is not always present in children, and it is sometimes nonspecifically elevated. Some EBV titers can be nonspecifically elevated as well; however, the above criteria are diagnostic of primary EBV infection.

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Infectious Mononucleosis and Encephalitis: Recovery of EB Virus from Spinal Fluid

PEDIATRICS ◽

10.1542/peds.64.2.257 ◽

1979 ◽

Vol 64 (2) ◽

pp. 257-258

Author(s):

Crystie C. Halsted ◽

R. Shihman Chang

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Transverse Myelitis ◽

Spinal Fluid ◽

Barr Virus ◽

Ebv Infection ◽

Direct Invasion ◽

Neurologic Disorders ◽

The Central Nervous System ◽

Epstein Barr

Epstein-Barr virus (EBV), the accepted cause of infectious mononucleosis (IM), has been associated with a variety of neurologic disorders including encephalitis, aseptic meningitis, transverse myelitis, Guillain-Barré syndrome, and Bell's Palsy.1,2 These neurologic syndromes may occur as the sole manifestation of EBV infection or together with the more typical clinical features of IM. It is unclear whether the central nervous manifestations of EBV result from direct invasion of the central nervous system by EBV or from a more indirect mechanism. This report describes the recovery of EBV from the spinal fluid of an 11-year-old boy with IM and encephalitis. CASE REPORT

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Infectious Mononucleosis in Children

PEDIATRICS ◽

10.1542/peds.55.6.897 ◽

1975 ◽

Vol 55 (6) ◽

pp. 897-897

Author(s):

Tooru Nakao ◽

Shunzo Chiba ◽

Shugeru Ikeda

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Barr Virus ◽

Ebv Infection ◽

Positive Antibody ◽

Epstein Barr

We agree with the opinion of Tamir et al.1 that the Paul-Bunnell and mononucleosis tests are of little value in children. In Japan, infectious mononucleosis is not common. Illness caused by Epstein-Barr virus (EBV) infection is rare after infancy because the positive antibody sera to EBV is 30% to 40% in the sera of infants between 1 and 24 months old. This increases rapidly to about 80% by 3 years of age.2 Primary EBV infection may occur before the age of 3 years.

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Clinical and laboratory presentation of EBV positive infectious mononucleosis in young adults

Epidemiology and Infection ◽

10.1017/s0950268803008550 ◽

2003 ◽

Vol 131 (1) ◽

pp. 683-689 ◽

Cited By ~ 42

Author(s):

I. GROTTO ◽

D. MIMOUNI ◽

M. HUERTA ◽

M. MIMOUNI ◽

D. COHEN ◽

...

Keyword(s):

Young Adults ◽

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Liver Enzymes ◽

Barr Virus ◽

Ebv Infection ◽

Elevated Liver Enzymes ◽

Disease Pattern ◽

Epstein Barr ◽

Low Sensitivity

Clinical descriptions of Epstein–Barr virus (EBV) positive infectious mononucleosis (IM) are rare and their results are inconsistent. Over a 4-year period, we prospectively studied 590 young adults with clinically suspected IM, all of whom were tested for the presence of EBV IgM antibodies. We investigated the demographical, clinical and laboratory features of subjects with positive EBV IgM serology and heterophile antibodies. Contrary to previous studies, we found a seasonal disease pattern with a peak incidence during summer months, and a lower-than-expected prevalence of lymphadenopathy (88·9%), leucocytosis (46·2%), atypical lymphocytosis (89·2%) and elevated liver enzymes (57·9%). The prevalence of hyperbilirubinemia was relatively high (14·9%). The classic triad of fever, sore throat and lymph-adenopathy had relatively low sensitivity (68·2%) and specificity (41·9%) for EBV infection. Our study provides a complete and updated description of the clinical and laboratory presentation of laboratory confirmed IM, which is important for both clinicians and epidemiologists.

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040 Acute cerebellar ataxia following epstein-barr virus infection

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-anzan.37 ◽

2019 ◽

Vol 90 (e7) ◽

pp. A14.1-A14

Author(s):

Stephanie L Barnes ◽

Bruce J Brew

Keyword(s):

Cerebellar Ataxia ◽

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Epstein Barr Virus Infection ◽

List Type ◽

Retrospective Case ◽

Barr Virus ◽

Ebv Infection ◽

Acute Cerebellar Ataxia ◽

Epstein Barr

IntroductionInfectious aetiologies such as acute Epstein-Barr virus (EBV) infection are in the differential diagnosis for acute cerebellar ataxia (ACA). This syndrome remains exceptionally rare and not well characterised in adults.e.g. 1 2MethodsA retrospective case review of a patient diagnosed with ACA following EBV infection with implications for pathogenesis and treatment.ResultsA 29-year-old Caucasian male presented with a three day history of ACA. Seven days prior he was diagnosed with infectious mononucleosis; bloodwork was consistent with acute EBV infection. These symptoms improved rapidly with oral prednisolone. He took no regular medications, drank alcohol moderately and had no significant family history.On examination, he was afebrile, ataxic and mildly dysarthric. Sensory examination was normal, particularly proprioception. Romberg’s test was negative. Remaining neurological and general examination was normal.Bloodwork showed mild liver dysfunction and positive ANA (titre 1/320, homogenous and speckled patterns). Immune screen was otherwise negative. Antineuronal antibody panel was negative in serum and CSF. CSF glucose was 3.1 mmol/L, protein 751 mg/L, albumin 523 mg/L, neopterin 24 nmol/L and B2 microglobulin 1.1 mg/L. The sample was acellular with negative EBV PCR (<500 copies/mL). Other infective serology and PCRs were also negative. MRI brain with gadolinium showed no abnormality.The patient received supportive care and was neurologically normal within three months.ConclusionsACA related to EBV is rare in adults. This report is important because it documents an adult case, other ACA causes have been rigorously excluded, resolution without antiviral therapy is detailed, and investigations support an immune-mediated pathogenesis.ReferencesMcCarthy CL, McColgan P, Martin P. Acute cerebellar ataxia due to Epstein-Barr virus. Pract Neurol 2012;12:238–240.Lascelles RG, Longson M, Johnson PJ, Chiang A. Infectious mononucleosis presenting as acute cerebellar syndrome. Lancet 1973;2:707.

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SH2D1A mutations in Japanese males with severe Epstein-Barr virus–associated illnesses

Blood ◽

10.1182/blood.v98.4.1268 ◽

2001 ◽

Vol 98 (4) ◽

pp. 1268-1270 ◽

Cited By ~ 35

Author(s):

Ryo Sumazaki ◽

Hirokazu Kanegane ◽

Maki Osaki ◽

Takashi Fukushima ◽

Masahiro Tsuchida ◽

...

Keyword(s):

Genetic Analysis ◽

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Genetic Disorder ◽

Lymphoproliferative Disease ◽

Barr Virus ◽

Ebv Infection ◽

Sporadic Cases ◽

Epstein Barr ◽

Acute Infectious Mononucleosis

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1Amutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP.

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Infectious mononucleosis and Epstein-Barr virus

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399404008440 ◽

2004 ◽

Vol 6 (23) ◽

pp. 1-16 ◽

Cited By ~ 52

Author(s):

Eleni-Kyriaki Vetsika ◽

Margaret Callan

Keyword(s):

Infectious Mononucleosis ◽

Primary Infection ◽

Epstein Barr Virus ◽

Latent Infection ◽

Clinical Syndrome ◽

Primary Immune Response ◽

Barr Virus ◽

Glandular Fever ◽

Ebv Infection ◽

Epstein Barr

Epstein-Barr virus (EBV) is a γ-herpesvirus that infects over 90% of the human population worldwide. It is usually transmitted between individuals in saliva, and establishes replicative infection within the oropharynx as well as life-long latent infection of B cells. Primary EBV infection generally occurs during early childhood and is asymptomatic. If delayed until adolescence or later, it can be associated with the clinical syndrome of infectious mononucleosis (also known as glandular fever or ‘mono%rsquo;), an illness characterised by fevers, pharyngitis, lymphadenopathy and malaise. EBV infection is also associated with the development of EBV-associated lymphoid or epithelial cell malignancies in a small proportion of individuals. This review focuses on primary EBV infection in individuals suffering from infectious mononucleosis. It discusses the mechanism by which EBV establishes infection within its human host and the primary immune response that it elicits. It describes the spectrum of clinical disease that can accompany primary infection and summarises studies that are leading to the development of a vaccine designed to prevent infectious mononucleosis.

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Epidemiology of Epstein-Barr Virus infection and Infectious Mononucleosis in the United Kingdom

10.1101/2020.01.21.20018317 ◽

2020 ◽

Author(s):

Ashvin Kuri ◽

Benjamin Meir Jacobs ◽

Nicola Vickaryous ◽

Julia Pakpoor ◽

Jaap Middeldorp ◽

...

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Antibody Responses ◽

Epstein Barr Virus Infection ◽

List Type ◽

White Ethnicity ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

The Uk

AbstractBackgroundEpstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ∼95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Over recent decades, the age of primary EBV infection has become later, largely due to improved sanitation and living conditions.Methods and findingsFirst, we conducted a sero-epidemiological survey of healthy volunteers between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. 1982 of 2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased monotonically with age, and increased more among females than males during adolescence (ages 10 – 15). Second, we conducted a retrospective review of Hospital Episode Statistics to determine changes in Infectious Mononucleosis (IM) incidence over time. Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. Exposures associated with lower risk of IM were elevated BMI (Overweight OR 0.80 [0.75 to 0.86], obese OR 0.63 [0.57 to 0.70]), non-white ethnicity (Black OR 0.21 [0.18 to 0.23], Asian OR 0.14 [0.13 to 0.16], Other ethnicity OR 0.22 [0.19 to 0.25]), and a history of smoking (OR 0.87 [0.83 to 0.92]), whereas affluence was associated with a higher risk of IM (per increase in IMD decile OR 1.15 [1.13 to 1.17]. Finally, we used ELISA to determine antibody responses to common pathogens and vaccine antigens among EBV-seronegative individuals. EBV-seronegative donors did not display diminished serum antibody responses to pertussis, rubella, or varicella compared to EBV-seropositive donors.ConclusionsIn this study we make several important observations on the epidemiology of EBV infection in the UK. We find that overall EBV seroprevalence in the UK appears to have increased, and that the sharp increase in EBV seropositivity takes places earlier among females than males. We find that the incidence of IM requiring hospitalisation is increasing. We find that exposures associated with prevalent IM in a diverse population include white ethnicity, affluence, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and encountered pathogens do not seem to be diminished among EBV-seronegative individuals, which is a theoretical counter-argument to developing EBV vaccines. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.Key messages-Epstein-Barr Virus (EBV) is a ubiquitous virus which infects over 95% of the world’s population. The majority of infection is silent and without consequence. In a subset of individuals, EBV is thought to play a role in the pathogenesis of autoimmune disease and haematological cancers.-During childhood and adolescence, EBV seroprevalence increased monotonically with age from 0-5 (67.8% females, 72.0% males) to 20-25 (96.4% females, 95.5% males)-The incidence of Infectious Mononucleosis (IM) leading to hospital admission has increased over the past decade-Exposure associated with IM in a large, diverse East London cohort (n>1,000,000) were low BMI, never-smoking, white ethnicity, and affluence.

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