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Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles.

ABSTRACT: To aid understanding of primary EBV infection, we have performed an in depth analysis of EBV-infected cells and of local immune cells in tonsils from infectious mononucleosis (IM) patients. We show that EBV is present in approximately 50% of B-cells showing heterogeneous patterns of latent viral gene expression probably reflecting different stages of infection. While the vast majority of EBV+ cells are B-cells, around 9% express T-cell antigens, with a predominance of CD8+ over CD4+ cells. PD-L1 was expressed by a median of 14% of EBV+ cells. The numbers of EBER+PD-L1+ cells were directly correlated with the numbers of EBER+CD3+ and EBER+CD8+ cells suggesting a possible role for PD-L1 in EBV infection of T-cells. The microenvironment of IM tonsils was characterized by a predominance of M1-polarized macrophages over M2-polarized cells. However, at the T-cell level, a heterogeneous picture emerged with numerous Th1/cytotoxic cells accompanied and sometimes outnumbered by Th2/regulatory T-cells. Further, we observed a direct correlation between the numbers of Th2-like cells and EBV- B-cells. Also, a prevalence of cytotoxic T-cells over Th2-like cells was associated with an increased viral load. These observations point to contribution of B- and Th2-like cells to the control of primary EBV infection. 35% of CD8+ cells were differentiated CD8+TBET+ cells, frequently detected in post-capillary venules. An inverse correlation was observed between the numbers of CD8+TBET+ cells and viral load suggesting a pivotal role for these cells in the control of primary EBV infection. Our results provide the basis for a better understanding of immune reactions in EBV-associated tumors.

SUBMITTER: Barros MHM

PROVIDER: S-EPMC6391352 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles.

Barros Mário Henrique M MHM Vera-Lozada Gabriela G Segges Priscilla P Hassan Rocio R Niedobitek Gerald G

Frontiers in immunology 20190220

To aid understanding of primary EBV infection, we have performed an in depth analysis of EBV-infected cells and of local immune cells in tonsils from infectious mononucleosis (IM) patients. We show that EBV is present in approximately 50% of B-cells showing heterogeneous patterns of latent viral gene expression probably reflecting different stages of infection. While the vast majority of EBV+ cells are B-cells, around 9% express T-cell antigens, with a predominance of CD8+ over CD4+ cells. PD-L1 ...[more]

PMID: 30842768

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Project description:BackgroundInfectious mononucleosis (IM) is a common adverse presentation of primary infection with Epstein-Barr virus (EBV) in adolescence and later, but is rarely recognized in early childhood where primary EBV infection commonly occurs. It is not known what triggers IM, and also not why IM risk upon primary EBV infection (IM attack rate) seemingly varies between children and adolescents. IM symptoms may be severe and persist for a long time. IM also markedly elevates the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons. The way IM occurrence depends on age and sex is incompletely described and hard to interpret etiologically, because it depends on three quantities that are not readily observable: the prevalence of EBV-naϊve persons, the hazard rate of seroconverting and the attack rate, i.e. the fraction of primary EBV infections that is accompanied by IM. We therefore aimed to provide these quantities indirectly, to obtain epidemiologically interpretable measures of the dynamics of IM occurrence to provide etiological clues.Methods and findingsWe used joint modeling of EBV prevalence and IM occurrence data to provide detailed sex- and age-specific EBV infection rates and IM attack rates and derivatives thereof for a target population of all Danes age 0-29 years in 2006-2011. We demonstrate for the first time that IM attack rates increase dramatically rather precisely in conjunction to typical ages of puberty onset. The shape of the seroconversion hazard rate for children and teenagers confirmed a priori expectations and underlined the importance of what happens at age 0-2 years. The cumulative risk of IM before age 30 years was 13.3% for males and 22.4% for females. IM is likely to become more common through delaying EBV infection in years to come.ConclusionsThe change in attack rate at typical ages of puberty onset suggests that the immunologic response to EBV drastically changes over a relatively short age-span. We speculate that these changes are an integrated part of normal sexual maturation. Our findings may inform further etiologic research into EBV-related diseases and vaccine design. Our methodology is applicable to the epidemiological study of any infectious agent that establishes a persistent infection in the host and the sequelae thereof.

Project description:BackgroundEpstein-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. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future.MethodsWe conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. 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.Results1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking.ConclusionsWe report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

Dataset Information

Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles.

Publications

Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles.

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