Epstein-Barr Virus Infection Research Articles

Sinus arrest and syncope in a young patient with Epstein-Barr Virus (EBV) infection: a case report

Abstract Background Emerging evidence suggests a potential link between Epstein-Barr virus (EBV) infection and cardiovascular diseases. However, the impact of EBV infection on the development of arrhythmias and conduction abnormalities remains to be fully clarified. Case summary We present a case report of a healthy 38-year-old Caucasian male who underwent an occupational medicine visit, during which a resting ECG showed numerous premature ventricular contractions (PVCs). He was later prescribed a stress test. During the test, he experienced a sinus arrest of 6.5 seconds with true syncope during the recovery phase. EBV infection was the only concomitant pathological finding observed during subsequent diagnostic investigations. Initially, it was necessary to rule out all possible cardiac causes of the event, especially in such a young patient. Comprehensive cardiac evaluations, including ECG, echocardiography, cardiac computed tomography (CCT), cardiac magnetic resonance (CMR), and electrophysiological studies, were normal. After two months, both the resting ECG and stress test were completely normal. The final diagnosis for the patient was “reflex cardioinhibitory syncope”. Accordingly, a pacemaker (PMK) device was not implanted, as the patient was under 40 years old and had no history of recurrent syncope, in accordance with European Guidelines. Discussion Temporary conditions that may cause conduction abnormalities are a contraindication to PMK implantation. Therefore, it is crucial to always consider EBV infection in the differential diagnosis of cardiac conduction disorders. One hypothesis is that EBV may have specifically affected the sinoatrial node and a few right ventricular outflow tract cells without causing myocarditis signs.

Identification and validation of a novel signature based on immune‑related genes from epithelial cells to predict prognosis and treatment response in patients with lung squamous cell cancer by integrated analysis of single‑cell and bulk RNA sequencing.

Epithelial cells are associated with tumor immunity through interstitial transformation, yet the role of epithelial immune-related genes (EIGs) in this process remains unclear. Comprehending the mechanisms behind EIGs within lung squamous cell carcinoma (LUSC) may offer an explanation to these issues. The present study aimed to explore the biological role of EIGs in patients with LUSC. Based on data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, a survival model and nomogram was established. This model and nomogram were used to study the mechanism of EIGs in LUSC and its medical significance by enrichment analysis, tumor microenvironment, immune cell infiltration and immune function correlation analysis. Finally, reverse transcription-quantitative PCR (RT-qPCR) and external dataset were used to assess the expression of the EIGs. The survival model was used to develop 4 EIGs as predictors for patient outcomes. Survival curves revealed that higher risk patients had more negative outcomes. This model and the nomogram developed based entirely on this model had an accurate prognosis predictive LUSC. The enrichment analysis indicated that pathways related to antigen processing and presentation, as well as Epstein-Barr virus infection, were prevalent in the high-risk populations. The research on immune infiltration demonstrated a notable rise in activated dendritic cells and neutrophils in the high-risk group. Furthermore, the results revealed that the high-risk populations are particularly susceptible to the effects of afureserpine, gefitinib and savolitinib. Finally, the outcomes of RT-qPCR were consistent with those of the bioinformatics analysis. In conclusion, the risk evaluation model and nomogram are effective in forecasting the prognosis and guiding drug selection for patients with LUSC. A worse prognosis in patients with high risk may be associated with certain viral infections and antigen processing and presentation.

Interpreting the role of epigallocatechin-3-gallate in Epstein-Barr virus infection-mediated neuronal diseases.

The increasing prevalence of neurodegenerative diseases is a formidable task due to their multifactorial causation and treatments limited to disease maintenance and progression. Epstein-Barr virus (EBV) is reported to be involved with neuropathologies; previous studies from our group suggested the effective binding of epigallocatechin-3-gallate (EGCG) with EBV nuclear antigen 1 (EBNA1) and glycoprotein H (gH). Therefore, in the current study, we evaluated the anti-EBV effect of ECGG on the neuronal cells. EBV-GFP exhibited a decline after EGCG treatment. We have observed a decrease in specific latent and lytic cycle genes. EBNA1 unravelled attenuation at day 1 (D1), whereas EBNA3B, EBNA3C, BMRF1, BZLF1, and gp350 showed major downregulation in D3 compared to EBV infection. Notably, EBNA-LP has shown mitigation in both the considered time points. Inflammatory and chemokine moieties like IL-6, CCR1, CCR3, and CCR5 declined upon EGCG treatment, while IL-10 exhibited elevation. Transcription factor STAT3 and NF-kB were decreased, especially in the pre-EGCG treated samples. Subsequently, restoration in the mitochondrial membrane potential was observed after EGCG treatment. We observed an increase in the mitochondrial fission genes like DRP1 and MiD49, and not many regulations were observed in the mitochondrial fusion genes except MFN2. Furthermore, the CytC, CytC oxidase, MAVS, ANT, and SDH exhibited elevation upon EGCG treatment, while ATPsyn and ABAD showed downregulation. Dysfunction of mitochondria is further related to apoptosis of neurons. Herein, we were keen to examine the level of amyloid-precursor protein (APP), and it has also indicated declined after EGCG treatment. Altogether, the current study demonstrated the anti-EBV effect of EGCG by subsiding the EBV-mediated inflammation and amendments in the neuropathological markers.

P1204 Childhood EBV infection is protective against IBD, while adulthood EBV infection is not: a population-based cohort study

Abstract Background Emerging data indicate a role of Epstein Barr Virus (EBV) infection in immune-mediated diseases risk. However, its role in inflammatory bowel disease (IBD) risk remains to be elucidated. Methods We conducted a nationwide population-based cohort study leveraging cross-linked Danish registers consisting of individuals with a record of being tested for EBV between January 1, 2008 and August 31, 2020. We determined the impact of previous EBV infection, active IBV infection, and no EBV infection on IBD risk, based on EBV serological tests, using adjusted Cox proportional hazards regression analyses after adjusting for sex, type of test, year of test, and age at test. We also determined the impact of age at infection, categorized as early or late childhood or adulthood (0-12, 13-20, and ≥21 years, respectively). Results Of 20,386 individuals included in the study who were followed from the first EBV test for a median (IQR) of 3.93 (2.18-5.95) years, 250 developed IBD. In the overall analysis, there were null associations between prior or current EBV infection and IBD risk. In analyses stratified by age, EBV infection in early and late childhood were associated with a protective effect against IBD, although not statistically significant in the former group (aHR 0.81, 95% CI 0.40, 1.66 and 0.50, 95% CI 0.26, 0.95, respectively). This association was driven by an increase in the risk of Crohn’s disease (CD), but not ulcerative colitis (aHR 0.36, 95% CI 0.15, 0.87 and aHR 0.82, 95% CI 0.32, 2.11, respectively). Among adults, while EBV infection was not associated with IBD risk (aHR 2.17, 95% CI 0.71, 6.62), the effect estimate was in the opposite direction relative to that in childhood, suggesting a potentially increased risk. Conclusion In a nationwide cohort, childhood EBV infection was protective against CD. Adulthood EBV infection was not protective, and possibly associated with increased IBD risk, although this was not statistically significant. Validation studies will help elucidate further.

P1334 Acute Severe Ulcerative Colitis: When Epstein-Barr Virus Joins Forces with Clostridioides difficile

Abstract Background We report the case of a 47-year-old female presenting with bloody, mucous diarrhea (10 bowel movements per day), generalized colicky abdominal pain persisting for two months, and significant weight loss of 5 kg within one month. Upon admission, the patient was normotensive, tachycardic (heart rate: 109 bpm), and febrile (temperature: 38.7ºC). Laboratory tests revealed hemoglobin of 12.4 g/dL, leukocyte count of 134,000/μL, platelet count of 537,000/μL, hypoalbuminemia (2.2 g/dL), and elevated C-reactive protein (CRP, 20.4 mg/dL), without evidence of hyperlactatemia. Methods Abdominal computed tomography (CT) demonstrated colonic dilation, primarily affecting the transverse colon, along with thickening of the descending colon wall. Rectosigmoidoscopy showed edematous mucosa with spontaneous bleeding and multiple deep ulcerations. The diagnosis of Severe Acute Ulcerative Colitis was established based on clinical, endoscopic, and radiological findings (Truelove & Witts score: severe; Mayo endoscopic subscore: 3), and intravenous corticosteroid therapy was initiated. Tests for Clostridioides difficile toxin A and B, as well as antigen, were positive, prompting treatment with vancomycin, as fidaxomicin was unavailable. Rectosigmoidoscopic biopsies confirmed active Clcerative Colitis and revealed the presence of Epstein-Barr virus (EBV) through in situ hybridization, consistent with EBV infection. Cytomegalovirus (CMV) was excluded in the biopsies, and ganciclovir therapy was started. Results On day three of corticosteroid therapy, due to a lack of response per the Oxford score, infliximab was initiated. Despite two doses, the patient persisted with seven bloody bowel movements daily, tachycardia, and hypotension, alongside transverse colon dilation (7.6 cm). This clinical course necessitated an emergency laparoscopic total proctocolectomy with Brooke-type ileostomy. Histopathological examination of the surgical specimen revealed microscopic changes characteristic of ulcerative colitis, predominantly affecting the transverse, descending, sigmoid colon, and rectum, with lesser involvement of the cecum and ascending colon. At the twelve-month follow-up, the patient remained asymptomatic. Conclusion EBV colitis is rare in patients not undergoing immunosuppressive therapy, as demonstrated in this case. While CMV testing in ulcerative colitis patients is widely recognized as essential, screening for EBV in intestinal mucosa is not routinely performed.This case underscores the importance of investigating coinfections, including CMV, C. difficile, and EBV, in patients experiencing acute exacerbations of ulcerative colitis. EBV infection is associated with symptom exacerbation, poorer prognosis, and an increased likelihood of colectomy. References 1 -Afzal M, Nigam GB. EBV colitis with ulcerative colitis: A double whammy. BMJ Case Rep. 2018;2018:1–3. 2 -Zhang H, Zhao S, Cao Z. Impact of Epstein–Barr virus infection in patients with inflammatory bowel disease. Front Immunol. 2022;13(October):1–15. 3 -Spinelli A, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. J Crohn’s Colitis. 2022;16(2):179–89.

OP26 Disentangling the role of HLA proteins in shaping the T-cell repertoire in Inflammatory Bowel Disease using CDR3-QTL analysis

Abstract Background The HLA region leads in the number of the strongest genetic associations for chronic immune-mediated diseases, including Inflammatory Bowel Disease1. Despite decades of research, the role of HLA in modulating chronic T cell-mediated responses remains unclear. HLA proteins present antigens for recognition by T cell receptors (TCRs). TCRs bear six complementarity determining regions (CDR), with the most variable CDR3 of the beta chain (CDR3b) due to a V(D)J recombination. The importance of CDR3 is determined by its direct interaction and recognition of antigens. Recent work by Ishigaki et al.2 identified that HLA-DRB1 site 13 influences the amino acid composition of CDR3b. Building on this, we extended the mapping between HLA sites and the CDR3b region to detect HLA sites that significantly contribute to the amino acid composition of CDR3b in IBD TCR repertoires. Methods We performed a comprehensive CDR3-QTL association analysis based on multivariate multiple linear regressions on a large dataset of ~2,000 paired HLA and TCR repertoires of healthy donors (n = 767) and IBD patients (n = 1188: 786 CD and 402 UC) using the analytical framework of Ishigaki et al.2 Results We discovered multiple novel HLA-DRB1 and HLA-DQ sites with distinct influences on TCRs. HLA-DRB1 sites 11 and 57 and DQB1 sites 57 and 71, located in antigen-binding pockets, strongly influence CDR3 composition in the IBD cohort. Notably, these effects were more pronounced in Crohn’s disease than in ulcerative colitis. HLA-DRB1 sites 67 and 73 and site 55 in DQB1 significantly influenced CDR3 composition only in healthy donors. HLA-DRB1 sites 13 and 71 and DQB1 site 87 were observed in both datasets, suggesting shared mechanisms irrespective of disease.The structural analysis revealed that healthy-specific sites directly interact with TCR, while common and IBD-specific sites predominantly occupy antigen-binding pockets. Conclusion Our study extensively identifies novel HLA sites that influence the most variable region in TCR - CDR3b in IBD patients. Our findings propose two distinct mechanisms by which HLA influences the CDR3: (1) direct TCR binding in TCRs (2) antigen-driven modulation in IBD-specific and common sites. The majority of identified HLA sites align with the loci previously associated with autoimmune diseases, and have been previously linked to common infections, particularly Epstein-Barr virus infection, suggesting that HLA influences CDR3 composition through both antigen-driven and direct TCR interactions.

An exploratory study on the differential diagnostic indicators between adult systemic EBV-positive T-cell lymphoproliferative disorders and angioimmunoblastic T-cell lymphoma with multiple EBV infections

BackgroundThe differential diagnosis between adult systemic EBV-positive T-cell lymphoproliferative disorders (EBV+ T-LPD) and angioimmunoblastic T-cell lymphoma (AITL) with multiple EBV infections is difficult, and distinguishing between the two has become a diagnostic challenge for pathologists. Given that the clinical treatment plans are different, an accurate diagnosis is a prerequisite to ensure effective treatment, therefore, it is extremely necessary and meaningful to find effective pathological indicators for distinguishing between two diseases.MethodsWe present a retrospective study comparing 7 cases of adult EBV+ T-LPD and 16 cases of AITL with multiple EBV infections diagnosed at our institution from 2017 to 2022. Differences in immunophenotype, type of EBV-infected cells, clonality and gene mutations between the two groups of cases were compared by immunohistochemical staining, double-label staining, TCR gene rearrangement and next-generation sequencing analysis.Results7 cases of adult EBV+ T-LPD: all cases had no more than 1 T follicular helper (THF) marker was expressed, and there were significantly more EBER+/CD3 + cells than EBER+/CD20 + cells; 5 cases had mutation detection results, in which only 1 had the characteristic KMT2D mutation, 2 had TET2 mutations, and no common mutations such as DDX3X were detected.16 cases of AITL with multiple EBV infections: all cases were found to express at least 2 TFH markers, with 87% of them expressing at least 3 TFH markers., and had significantly more EBER+/CD20 + cells than EBER+/CD3 + cells; 4 cases had mutation test results, with mutated high-frequency genes being TET2 (100%, and all of them had 2 or more TET2 mutations) and RHOA G17V (100%), DNMT3A mutation occurred in 2 cases (50%), and IDH2 R172 mutation occurred in 1 case (25%).ConclusionsWe found that the expression pattern of TFH markers, the types of cells predominantly infected by EBV and the different mutations can all be used as effective pathological indicators for distinguishing between two diseases.

Two siblings with monogenic lupus due to C1qC deficiency and case based review.

Monogenic lupus is an extremely rare clinical condition in children. Defects in the complement pathway are the most common causes of monogenic lupus. C1qC deficiency is one of the defects in this pathway and is even rarer. Herein, we present two cases of monogenic lupus diagnosed with C1qC deficiency in siblings. In addition, a literature search was conducted for articles on monogenic lupus due to C1qC deficiency. We found 14 articles. Our literature search identified 17 paediatric patients with monogenic lupus associated with C1qC deficiency. 10 (58%) of the reported patients were female. The median age at diagnosis of patients in the literature was 3years. Mucocutaneous involvement was remarkable in all cases of C1qC deficiency. Joint involvement was reported in about half of the cases. Approximately half of the reported cases has suffered from recurrent infections. 38% of the cases have had CNS involvement and 25% of these had nephritis. While both of our patients had mucocutaneous involvement, one of our patients had recurrent EBV infection. ANA was positive, anti-dsDNA was negative, C3-C4 levels were normal in almost all cases in the reported cases. The anti-Sm and anti-SSA positivities of these cases were also remarkable. These laboratory findings were similar in our patients. The G34R mutation of the C1qC gene is the most common genetic defect identified to date. We found a GRCh38/Hg38 1p36.12 homozygous deletion in the C1qC gene in both of our patients. It is necessary to investigate the causes of monogenic lupus in patients with early-onset lupus, history of consanguineous marriages, and antibody positivity.

Epstein-Barr virus Infection Exacerbates Ulcerative Colitis by Driving Macrophage Pyroptosis via the Upregulation of Glycolysis

Abstract Background Epstein-Barr virus (EBV) infection is associated with clinical symptoms, treatment response, need for surgical intervention, and an enhanced likelihood of lymphoma among patients with ulcerative colitis (UC). However, existing studies have primarily concentrated on the epidemiological and clinical associations between EBV and UC, leaving the mechanisms by which EBV exacerbates colitis poorly understood. Methods Clinical specimens of UC patients with EBV infection and a mouse model of dextran sulfate sodium (DSS)-induced colitis with concurrent murine γ-herpesvirus 68 (MHV-68) infection were utilized to investigate the relationship between EBV infection and macrophage pyroptosis. In vivo, adoptive transfer of MHV-68-induced macrophages and macrophage depletion were performed to elucidate the underlying mechanisms. In vitro, myeloid leukemia mononuclear cells of human (THP-1) and macrophages derived from mouse bone marrow (BMDMs) were stimulated with EBV and MHV-68, respectively, to assess macrophage pyroptosis and glycolysis. Results EBV-induced activation of macrophage pyroptosis was positively correlated with clinical disease activity in UC patients. Furthermore, MHV-68 infection activated pyroptosis by upregulating Gasdermin D, NLRP3, interleukin-1β, and interleukin-18 in colonic tissues and peritoneal macrophages of mice with colitis. In vitro, EBV and MHV-68 also mediated activation of pyroptosis in human THP-1 cells and mouse BMDMs, respectively. Additionally, the adoptive transfer of MHV-68-induced BMDMs aggravated murine colitis, whereas macrophage depletion attenuated MHV-68-induced intestinal injury. Mechanistically, MHV-68 promoted macrophage pyroptosis by upregulating glycolysis, while the glycolysis inhibitor, 2-Deoxy-d-glucose, blocked this process in vitro. Conclusion EBV infection exacerbates UC by driving macrophage pyroptosis through upregulation of glycolysis, indicating a potential therapeutic approach to mitigate EBV-induced intestinal inflammation.

Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency.

X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in the SH2D1A or XIAP genes, are characterized by the inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases in each, lymphomas occur at high rates with XLP-1 but not with XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis, in contrast to all other described congenital conditions that result in heightened susceptibility to EBV, remains a key open question. To gain insights, we cross-compared newly EBV infected versus immune stimulated B-cells from XLP-2 patients or upon XIAP CRISPR knockout, relative to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected primary human B-cells, though had no impact on proliferation of B-cells stimulated by CD40 ligand and interleukin-21 or upon established EBV-immortalized lymphoblastoid cell lines (LCLs). B-cells from XLP-2 patients or in which XIAP was depleted by CRISPR editing exhibited a markedly lower EBV transformation efficiency than healthy control B-cells. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, whose effects on transforming B-cell death were counteracted by XIAP. In the absence of XIAP, EBV infection triggered high rates of apoptosis, not seen with CD40L/IL-21 stimulation. Moreover, inflammatory cytokines are present at high levels in XLP-2 patient serum with fulminant EBV infection, which heightened apoptosis induction in newly EBV-infected cells. These findings highlight the crucial role of XIAP in supporting early stages of EBV-driven B-cell immortalization and provide insights into the absence of EBV+ lymphoma in XLP-2 patients.

Multifocal osteochondromatous proliferation and paraneoplastic hematologic dyscrasia in the context of latent Epstein-Barr virus reactivation: a case of oncologic and infectious pathophysiology.

This case report describes a 15-year-old male with multifocal osteochondromatous proliferation and paraneoplastic hematologic dyscrasia, linked to latent Epstein-Barr virus reactivation. Radiographic and advanced imaging revealed widespread skeletal lesions consistent with osteochondromatosis. Hematologic evaluation indicated pancytopenia with dysplastic megakaryocytes and marrow infiltration. Immunohistochemical staining confirmed latent Epstein-Barr virus infection, suggesting its role in the pathogenesis of both the osteochondromatous and hematologic abnormalities. This case highlights the correlation between Epstein-Barr virus reactivation, bone proliferation, and paraneoplastic hematologic processes, which we believe has not yet been reported in the literature, emphasizing the need for a comprehensive diagnostic approach.

Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) in Gastric Cancers, with Special Reference to Gastric Cancer at a Young Age-A Pilot Study in Poland.

Gastric cancer (GC) is one of the most common cancers in the world. It is a multi-factorial disease influenced by both genetic and environmental factors such as diet, obesity, radiation exposure, and infectious agents. Viral infections usually lead to chronic inflammation, which can initiate the development of cancers. To date, only a few studies have been published about Epstein-Barr virus (EBV) and human papillomavirus (HPV) infections in the context of the development of GC. In particular, research on the development of cancer among people under 45 years of age, including the impacts of EBV and HPV, is rare, and clear results have not been obtained. The aim of this study was to analyze the frequency of occurrence of EBV and HPV in GC, particularly in early-onset gastric cancer (EOGC). Tissue material from 135 patients with GC, including 84 men and 51 women, was examined. RT-PCR was performed to detect EBV, and PCR was performed to detect HPV. There were no significant impacts of EBV and HPV infections on any subtype of GC. There was also no statistically significant dependence of gender and location of the tumor on any subtype of GC. Further research on the impacts of infectious agents such as EBV and HPV on GC should be conducted using larger populations.

Targeting EBV Episome for Anti-Cancer Therapy: Emerging Strategies and Challenges.

As a ubiquitous human pathogen, the Epstein-Barr virus (EBV) has established lifelong persistent infection in about 95% of the adult population. The EBV infection is associated with approximately 200,000 human cancer cases and 140,000 deaths per year. The presence of EBV in tumor cells provides a unique advantage in targeting the viral genome (also known as episome), to develop anti-cancer therapeutics. In this review, we summarize current strategies targeting the viral episome in cancer cells. We also highlight emerging technologies, such as clustered regularly interspersed short palindromic repeat (CRISPR)-based gene editing or activation, which offer promising avenues for selective targeting of the EBV episome for anti-cancer therapy. We discuss the challenges, limitations, and future perspectives associated with these strategies, including potential off-target effects, anti-cancer efficacy and safety.

Molecular characterization of EBV-associated primary pulmonary lymphoepithelial carcinoma by multiomics analysis

BackgroundPrimary pulmonary lymphoepithelial carcinoma (pLEC) is a subtype of non-small cell lung cancer (NSCLC) characterized by Epstein-Barr virus (EBV) infection. However, the molecular pathogenesis of pLEC remains poorly understood.MethodsIn this study, we explored pLEC using whole-exome sequencing (WES) and RNA-whole-transcriptome sequencing (RNA-seq) technologies. Datasets of normal lung tissue, other types of NSCLC, and EBV-positive nasopharyngeal carcinoma (EBV+-NPC) were obtained from public databases. Furthermore, we described the gene signatures, viral integration, cell quantification, cell death and immune infiltration of pLEC.ResultsCompared with other types of NSCLC and EBV+-NPC, pLEC patients exhibited a lower somatic mutation burden and extensive copy number deletions, including 1p36.23, 3p21.1, 7q11.23, and 11q23.3. Integration of EBV associated dysregulation of gene expression, with CNV-altered regions coinciding with EBV integration sites. Specifically, ZBTB16 and ERRFI1 were downregulated by CNV loss, and the FOXD family genes were overexpressed with CNV gain. Decreased expression of the FOXD family might be associated with a favorable prognosis in pLEC patients, and these patients exhibited enhanced cytotoxicity.ConclusionCompared with other types of NSCLC and NPC, pLEC has distinct molecular characteristics. EBV integration, the aberrant expression of genes, as well as the loss of CNVs, may play a crucial role in the pathogenesis of pLEC. However, further research is needed to assess the potential role of the FOXD gene family as a biomarker.

Epstein-Barr virus (EBV) and systemic lupus erythematosus (SLE) association in serological studies

Over the past 50 years, a substantial body of research revealed an association between Epstein-Barr virus (EBV), and various aspects of EBV infection, with multiple autoimmune diseases. Growing evidence points to EBV as a potential co-factor in systemic lupus erythematosus (SLE) and several mechanisms have been proposed to explain this relationship, however there is as yet no conclusive proof of causality. This literature review constitutes an introduction into the subject and attempts to outline the findings on the EBV-SLE connection, focusing mostly on the evidence provided by serological studies.

Characteristics and Clinical Significance of Gut Microbiota in Patients With Epstein-Barr Virus-Associated Liver Dysfunction.

Infectious mononucleosis (IM) is mainly triggered by Epstein-Barr virus (EBV) infection. There are few studies on the role of the gut microbiota in IM and EBV-associated liver dysfunction. The aim of this study was to investigate the characteristics of the gut microbiota in the EBV-associated liver dysfunction and to evaluate the relationship between the severity of gut microbiota dysbiosis and cytokine levels. A case-control study was performed. Individuals meeting the inclusion and exclusion criteria for EBV-induced IM were enrolled and their fecal and blood samples were collected. The V3-V4 region of the 16s rDNA gene of fecal microbiota was sequenced; bioinformatics analysis including α-diversity, β-diversity, and linear discriminant analysis (LDA) effect size (LEfSe) was performed; and the correlation between bacteria and clinical indices was analysed. A total of 48 participants completed fecal and blood tests, including 18 IM, 11 EBV-associated liver dysfunction, 12 healthy children and 7 EBV-negative liver dysfunction. The α-diversity and β-diversity of the gut microbiota in the EBV-associated liver dysfunction was more than that in IM. The abundance of Granulicatella, Enterococcus, Atopobium and Acinetobacter increased, while the abundance of Prevotella, Sutterella, Collinsella, Desulfovibrio decreased in the EBV-associated liver dysfunction compared with the IM. The abundance of Enterococcus, Atopobium and Acinetobacter correlated positively with the levels of IL-1β, IL-6, TNF-α and CD8+ cytotoxic T lymphocytes%. Gut microbiota of EBV-associated liver dysfunction was significantly disturbed and associated with systemic immune response.

Implications of EBV-Encoded and EBV-Related miRNAs in Tumors.

Over 90% of people are infected with the human g-herpesvirus known as the Epstein- Barr virus (EBV). Cancers, such as gastric carcinoma, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and Burkitt lymphoma, are thought to be linked with EBV. It is noteworthy that the first virus discovered that encodes microRNAs (miRNAs) was EBV, and these miRNAs show expression at the different phases of EBV infection. There is growing evidence that EBV-encoded miRNAs influence the growth of EBV-associated tumors. These EBV miRNAs, i.e., BamHI-H rightward fragment 1-derived microRNAs (BHRF1miRNA) and BamHI-A rightward fragment-derived microRNAs (BART miRNAs), are crucial for the persistence of viral infection and the avoidance of host defenses. Currently, significant advancements have been made in analyzing the microRNAs that are found in the duration of EBV infection, in vitro studies identified molecular targets of miRNAs and in vivo studies enhanced our understanding regarding the pathophysiology of these molecules. An extensive look into the pro-carcinogenic impact of microRNAs associated with EBV will increase our understanding of the molecular mechanisms of EBV-associated tumors. In this paper, we have highlighted the functions of miRNAs in EBV infection as well as recent developments in miRNA-based therapeutic and diagnostic approaches that could be useful for EBV-related malignancies. Significantly, targeted therapies against EBV miRNAs are advancing rapidly, with emerging approaches such as miRNA sponges, anti-miRNA oligonucleotides, and CRISPR/Cas9 technologies. These innovations indicate the imminent onset of a new era in the treatment of EBV-associated tumors.

Structural basis of Epstein-Barr virus gp350 receptor recognition and neutralization.

Epstein-Barr virus (EBV) is an oncogenic virus associated with multiple lymphoid malignancies and autoimmune diseases. During infection in B cells, EBV uses its major glycoprotein gp350 to recognize the host receptor CR2, initiating viral attachment, a process that has lacked direct structural evidence for decades. In this study, we resolved the structure of the gp350-CR2 complex, elucidated their key interactions, and determined the site-specific N-glycosylation map of gp350. Our findings reveal that CR2 primarily binds to gp350 through an electrostatically complementary and glycan-free interface and that the diversity of key residues in CR2 across different species influences EBV host selectivity mediated by gp350. With the confirmed binding, we constructed a CR2-Fc antibody analog that targets the vulnerable site of gp350, demonstrating a potent neutralization effect against EBV infection in B cells. Our work provides essential structural insights into the mechanism of EBV infection and host tropism, suggesting a potential antiviral agent.

Effect of Epstein-Barr Virus infection on gene regulation in immune cells of patients with Immune-Mediated Diseases.

It has been known that Epstein-Barr virus (EBV) can latently infect immune cells after the initial infection, and epidemiological studies have suggested its association with the onset of immune-mediated diseases (IMDs). However, the specific impact of EBV infection on IMDs pathology remains unclear. We quantified EBV load of B cell subsets (Naïve B cells, Unswitched memory B cells, Switched memory B cells, Double negative B cells, and Plasmablasts) in IMD patients as well as healthy control (HC) using bulk RNA sequencing data of 504 donors. The EBV load was clearly higher in IMD patients compared to HC. Furthermore, the wide range of EBV load in this dataset enabled us to assess the impact of EBV load on gene regulation. We found many examples of expression quantitative trait loci (eQTL) whose effects were associated with EBV load. Expression QTLs that exhibited larger effects with increasing EBV load were significantly overlapped with binding sites of transcription factors derived from the EBV genome. These EBV load-associated eQTLs exhibited high enrichment of systemic lupus erythematosus (SLE) GWAS signals, suggesting the mechanical link of EBV infection and the onset of the disease via gene regulation. These findings provide the first evidence of the influence of EBV infection on gene regulation in human primary cells and its association with the SLE onset and/or progression.

Distinct subtypes of post-transplant lymphoproliferative disorders: CHIP-like mutations in early lesions and substantial mutational differences between EBV-positive and EBV-negative diffuse large B-cell lymphomas.

Post-transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated a PTLD cohort (n = 50) consisting of 'early lesions' (infectious mononucleosis-like PTLD, plasmacytic and follicular hyperplasias), polymorphic PTLD and post-transplant diffuse large B-cell lymphomas (PT-DLBCL). The study also included 15 DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural and genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence insitu hybridisation and high-throughput sequencing were performed. Scarcity of viral infections other than Epstein-Barr virus (EBV) was observed. mIF revealed lower Treg infiltration in PT-DLBCL and high CD8+/PD1+ T cells in IS-DLBCL. MYC rearrangements were most common in PT-DLBCL, followed by IS-DLBCL and DLBCL, NOS, all EBV-negative. TP53 mutations were frequent in EBV-negative PT-DLBCL and DLBCL, NOS but absent in 'early lesions'. NOTCH1 mutations were predominant in PT-DLBCL (N1 DLBCL-subgroup). Gene expression profiling showed a significant overlap between 'early lesions' and polymorphic PTLD. The presence of clonal haematopoiesis of indeterminate potential (CHIP)-like mutations and the absence of immune-escape gene mutations in 'early lesions' suggest these disorders may represent clonal expansions driven by exogenic immunosuppression and/or EBV infection 'substituting' for mutations of the latter group of genes.