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Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the changes of Notch signaling molecules and Th22 cells in adult patients with infectious mononucleosis (IM), and assess the regulatory function of Notch...
OBJECTIVE
To investigate the changes of Notch signaling molecules and Th22 cells in adult patients with infectious mononucleosis (IM), and assess the regulatory function of Notch signaling inhibition to Th22 cells.
METHODS
Forty-two IM patients and twenty-one healthy controls were enrolled in this study. Their peripheral blood was collected, from which plasma and peripheral blood mononuclear cells (PBMCs) were isolated. Plasma interleukin (IL)-17 and IL-22 were measured by enzyme-linked immunosorbent assay. The percentages of CD3 CD4 IL-17 Th17 cells and CD3 CD4 IL-22 Th22 cells were investigated by flow cytometry. The mRNA relative levels corresponding to Th17 transcription factor retinoic acid related orphan receptor γt (RORγt), Th22 transcription factor aryl hydrocarbon receptor (AhR), and Notch signaling pathway molecules (including Notch receptors, Notch ligands, Notch downstream molecules) were semi-quantified by real-time PCR. CD4 T cells were purified and stimulated with γ-secretase inhibitor (GSI). Cellular proliferation, Th17 and Th22 percentage, IL-17 and IL-22 secretion, transcription factor mRNA were measured in response to GSI stimulation.
RESULTS
The relative expression levels of and mRNA in PBMCs of IM group were 13.58±3.18 and 4.73±1.16, respectively, which were significantly higher than 1.09±0.12 and 1.07±0.15 in PBMCs of control group (both < 0.001). However, there were no significant differences in relative expression levels of and mRNA between IM group and control group ( >0.05). The relative expression levels of Notch ligands (including and ) mRNA and Notch downstream molecules (including and ) were increased in IM group compared with control group (all < 0.001). In IM group, the Th17 and Th22 percentage were 5.03%±1.15% and 4.48%±1.29%, respectively, which were both higher than 4.36%±0.82% and 3.83%±0.55% in control group (both < 0.05). In IM group, the IL-17 and IL-22 level were (301.1±53.82) and (101.2±16.45) pg/ml, respectively, which were both higher than (237.2±72.18) and (84.75±11.83) pg/ml in control group (both < 0.001). In IM group, the relative expression levels of and mRNA were 1.25±0.22 and 1.21±0.12, respectively, which were both higher than 0.99±0.15 and 1.04±0.11 in control group (both < 0.001). There were no remarkable differences in CD4 T cell proliferation, Th17 percentage, IL-17 secretion, and relative expression level of mRNA between cells with GSI stimulation and without GSI stimulation ( >0.05). GSI stimulation reduced Th22 percentage, IL-22 secretion, and relative expression level of mRNA compared with non-stimulation (all < 0.05).
CONCLUSION
Notch signaling pathway regulates IL-22 secretion by CD4 T cells via AhR in IM patients. Notch-AhR-Th22 pathway may take part in the pathogenesis of IM.
Topics: Humans; Signal Transduction; Adult; Th17 Cells; Receptors, Notch; Interleukin-17; Interleukin-22; Nuclear Receptor Subfamily 1, Group F, Member 3; Infectious Mononucleosis; Interleukins; Herpesvirus 4, Human; Leukocytes, Mononuclear; Receptor, Notch1; Receptors, Aryl Hydrocarbon; CD4-Positive T-Lymphocytes
PubMed: 38926989
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.041 -
NPJ Vaccines Jun 2024Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that...
Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH/gL, gH/gL/gp42 or gp350 delivered by a cationic nanocarrier termed LION™. The lead candidate, encoding full-length gH/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8 T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION/repRNA-gH/gL is an ideal candidate vaccine for preventing EBV infection and/or related malignancies in humans.
PubMed: 38926438
DOI: 10.1038/s41541-024-00907-y -
Pathogens (Basel, Switzerland) Jun 2024This study investigates the impact of Epstein-Barr virus (EBV) infection on children's proteomes across different phases of the disease, utilising seventy-nine blood...
This study investigates the impact of Epstein-Barr virus (EBV) infection on children's proteomes across different phases of the disease, utilising seventy-nine blood samples categorised into three groups: EBV-naive patients, acute infectious mononucleosis (IM) cases, and convalescents followed up for 12 months post-IM. The aim is to identify proteins influenced by EBV infection, shedding light on the chronic processes triggered by the virus. The results reveal thirty-nine proteins distinguishing between naive patients and those with IM, including actin, lumican, peroxiredoxin-2, fibulin-1, gelsolin, and alpha-2-macroglobulin, which are involved in immune responses, cell adhesion, and inflammation. Elevated oxidative stress markers like peroxiredoxin-2 in IM patients suggest potential links to EBV's induction of reactive oxygen species. Increased levels of apolipoproteins A-I, A-IV, C-IV, and M during IM imply associations with viral infection, while complement system proteins (C1q, C1r, and C8 gamma chain) are also elevated, reflecting their role in the immune response and viral clearance. This study's focus on children provides unique insights into EBV's impact on young populations, emphasising proteomics' role in uncovering protein associations and understanding the virus's long-term consequences. However, specific relationships between identified proteins and EBV infection require further investigation.
PubMed: 38921769
DOI: 10.3390/pathogens13060471 -
BioRxiv : the Preprint Server For... Jun 2024Viral infection leads to heterogeneous cellular outcomes ranging from refractory to abortive and fully productive states. Single cell transcriptomics enables a high...
UNLABELLED
Viral infection leads to heterogeneous cellular outcomes ranging from refractory to abortive and fully productive states. Single cell transcriptomics enables a high resolution view of these distinct post-infection states. Here, we have interrogated the host-pathogen dynamics following reactivation of Epstein-Barr virus (EBV). While benign in most people, EBV is responsible for infectious mononucleosis, up to 2% of human cancers, and is a trigger for the development of multiple sclerosis. Following latency establishment in B cells, EBV reactivates and is shed in saliva to enable infection of new hosts. Beyond its importance for transmission, the lytic cycle is also implicated in EBV-associated oncogenesis. Conversely, induction of lytic reactivation in latent EBV-positive tumors presents a novel therapeutic opportunity. Therefore, defining the dynamics and heterogeneity of EBV lytic reactivation is a high priority to better understand pathogenesis and therapeutic potential. In this study, we applied single-cell techniques to analyze diverse fate trajectories during lytic reactivation in two B cell models. Consistent with prior work, we find that cell cycle and MYC expression correlate with cells refractory to lytic reactivation. We further found that lytic induction yields a continuum from abortive to complete reactivation. Abortive lytic cells upregulate NFκB and IRF3 pathway target genes, while cells that proceed through the full lytic cycle exhibit unexpected expression of genes associated with cellular reprogramming. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis.
AUTHOR SUMMARY / SIGNIFICANCE
Viral infections profoundly alter host cell biological programming in ways that potentiate disease. Epstein-Barr virus (EBV) is a particularly prevalent human pathogen associated with diverse cancers and several autoimmune disorders. EBV predominantly establishes latent infection in B cells and can promote B cell malignancies through functions of well-characterized latent oncoproteins. Aspects of the viral lytic cycle also clearly contribute to EBV-associated diseases, although pathologic roles of lytic reactivation are incompletely understood. Here we use single-cell techniques to examine cellular responses to EBV lytic reactivation in multiple B cell models. Consistent with prior studies, reactivation from latency is incomplete (abortive) in some cells and successful in others. Abortive and full lytic trajectories exhibit distinct biological responses that each may promote pathogenesis and reinforce bimodal latent-lytic control. Intriguingly, a portion on cells that proceed through the lytic cycle exhibits unexpected and striking expression of genes associated with cellular reprogramming, pluripotency, and self-renewal. Collectively, this study provides a valuable resource to understand diverse host-virus dynamics and fates during viral reactivation and identifies multiple modes of EBV lytic pathogenesis to investigate in future research.
PubMed: 38915538
DOI: 10.1101/2024.06.14.598975 -
Clinical Journal of Sport Medicine :... Jul 2024
Topics: Humans; Infectious Mononucleosis; Sports Medicine; Societies, Medical; United States; Sports
PubMed: 38914101
DOI: 10.1097/JSM.0000000000001224 -
Alternative Therapies in Health and... Jun 2024To analyze the manifestations of infectious mononucleosis and its impact on liver function in children.
OBJECTIVE
To analyze the manifestations of infectious mononucleosis and its impact on liver function in children.
METHODS
This retrospective study analyzed clinical data from 695 children with infectious mononucleosis (IM) who were hospitalized at the Department of Pediatrics, Chengdu First People's Hospital between January 1, 2017, and December 31, 2022. They were analyzed into two groups according to whether their ALT was greater than 40 U/L. Demographic variables, clinical features, and laboratory findings were collected from medical records. Statistical analyses were performed using the Statistic Package for Social Science (SPSS) 26.
RESULTS
A total of 695 children with infectious mononucleosis (IM)(409 males and 286 females) were included in the study. The age distribution was 161 infants (<3 years), 357 preschoolers (3-7 years), and 177 school-aged children (≥7 years). After clinical recovery, 61 cases had elevated liver enzymes. Asynchronous changes in AST and ALT were present in 18 children. The highest proportion of fever onset (75.2%) occurred in infancy (P = .00). Elevated AST, lymphocyte percentage and WBCs, age in school age, uncomplicated myocardial injury these were the risk factors for the development of liver injury in children with infectious mononucleosis. P values were .00, .048, .021, .000 and .002, respectively. 95% CIs were 65., 2-315.52, 1.01-3.48, 1.18- 7.37, 2.57-13.52 and 1.79-13.35, respectively.
CONCLUSIONS
The clinical features vary with sex and age. Children with IM who are school-aged, without myocardial injury, and have elevated WBC, lymphocyte percentage, and AST should be monitored for potential liver damage. Careful evaluation is necessary following clinical recovery to determine if vaccination is appropriate.
PubMed: 38904624
DOI: No ID Found -
Cells Jun 2024Primary Epstein-Barr virus (EBV) infection which can manifest as infectious mononucleosis (IM) is commonly acquired during childhood. EBV primarily invades B cells...
Primary Epstein-Barr virus (EBV) infection which can manifest as infectious mononucleosis (IM) is commonly acquired during childhood. EBV primarily invades B cells leading to a lytic reaction; the control of the infection is handled by natural killer and T cells in immunocompetent individuals. The infection has a wide spectrum of clinical findings and can lead to serious complications in patients with certain underlying immunological dysfunctions. We retrospectively investigated peripheral white blood cell populations' surface marker characteristics in IM using a comprehensive flow cytometry marker panel. Twenty-one cases of IM and seventeen EBV-seropositive cases without IM serving as controls were included. We observed novel alterations in lymphocyte, neutrophil, and monocyte populations. In addition to increased activated cytotoxic T cells and low B cells, we demonstrated high T-large granular lymphocyte (T-LGL) populations in IM cases. Furthermore, despite T cells' increased HLA-DR expression, another activation marker, CD11b, was lower in T-LGL populations. Monocytes showed increased CD16 expression; CD64 was higher in neutrophils. Our findings point to monocyte and neutrophil activation which may account for acute clinical features and may contribute to the understanding of IM immunobiology. Furthermore, they may serve as a useful tool in investigating inherited and post-transplant conditions characterized by deficiencies in controlling EBV infection.
Topics: Humans; Flow Cytometry; Male; Female; Epstein-Barr Virus Infections; Child; Leukocytes; Herpesvirus 4, Human; Adolescent; Adult; Infectious Mononucleosis; Monocytes; Child, Preschool; Neutrophils; Acute Disease; Retrospective Studies; Young Adult
PubMed: 38891094
DOI: 10.3390/cells13110963 -
Cureus May 2024Infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV), is a common viral illness among adolescents and young adults. IM typically presents with...
Infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV), is a common viral illness among adolescents and young adults. IM typically presents with symptoms such as fever, lymphadenopathy, and pharyngitis. We present a case of a 32-year-old woman who developed a maculopapular rash following ibuprofen administration, revealing an underlying undiagnosed IM. Laboratory investigations confirmed EBV infection. This represents the first documented case linking non-steroidal anti-inflammatory drugs (NSAIDs) to IM presentation. Awareness of this association is crucial for timely diagnosis and management, especially when evaluating patients with unexplained skin reactions to medications.
PubMed: 38883093
DOI: 10.7759/cureus.60329 -
Virology Journal Jun 2024Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the...
BACKGROUND
Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM).
METHODS
We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (T).
RESULTS
All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (r = 0.345, 0.418, and 0.356, respectively) within the first two weeks after T, but no correlation with the number of detectable EBV-reactive CD4+ T cells.
CONCLUSIONS
All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity.
Topics: Humans; Infectious Mononucleosis; Antigens, Viral; Herpesvirus 4, Human; Child; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes; Female; Male; Adolescent; Child, Preschool; Epitopes, T-Lymphocyte
PubMed: 38877590
DOI: 10.1186/s12985-024-02411-0 -
Epigenomics May 2024Epstein-Barr virus (EBV) infection is linked to various human diseases, including both noncancerous conditions like infectious mononucleosis and cancerous diseases such... (Review)
Review
Epstein-Barr virus (EBV) infection is linked to various human diseases, including both noncancerous conditions like infectious mononucleosis and cancerous diseases such as lymphoma and nasopharyngeal carcinoma. After the initial infection, EBV establishes a lifelong presence and remains latent in specific cells. This latent infection causes changes in the epigenetic marks known as histone methylation. Many studies have examined the role of histone methylation in different EBV-associated diseases, and understanding how EBV affects histone methylation can help us identify potential targets for epigenetic therapies. This review focuses on the research progress made in understanding histone methylation in well-studied EBV-associated diseases, intending to provide insights into potential strategies based on histone methylation to combat EBV-related ailments.
PubMed: 38869454
DOI: 10.1080/17501911.2024.2345040