Epstein-Barr Research Articles

POTENTIAL CAUSAL ASSOCIATION BETWEEN HUMAN CYTOMEGALOVIRUS INFECTION AND CHRONIC BACK PAIN: A ONE-SAMPLE MENDELIAN RANDOMIZATION STUDY

BackgroundChronic back pain (CBP) is a major cause of disability globally and its causes are multifactorial. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are human herpes viruses usually acquired in early life. About 50% and over 90% of the population worldwide have been infected with CMV and EBV, respectively. This study investigated a potential causal relationship between CMV infection and CBP.MethodUK Biobank participants provided information on CMV seropositivity and CBP status, which were available for both traits in 5,140 participants. We used EBV seropositivity as a negative control to identify confounding and inaccurate causal inference. A one-sample Mendelian randomization (MR) based on independent genetic variants predicting CMV and EBV positivity was conducted in Northern European participants. To validate the association further, the MR study was repeated using a CMV polygenic risk score (PRS).ResultsCMV GWAS revealed 86 independent SNPs having p-value < 2 × 10−4 for the one-sample MR. These SNPs were used to define genetically-predicted categories of CMV infection risk. CMV infection risk categories were significantly associated with CBP (OR = 1.150; 95% CI: 1.005–1.317, p-value = 0.043), findings which were confirmed using the CMV PRS (OR = 1.299; 95% CI: 1.141–1.479, p-value = 0.001). There was no causal association between EBV and CBP (p-value = 0.17).ConclusionOur results provide further evidence for a causal relationship between CMV infection and CBP. These results suggest a stratified approach to CBP may be useful, particularly in clinical trials and they shed light on underlying mechanisms in CBP.Conflicts of interestNo conflicts of interestSources of fundingNo funding obtainedAcknowledgementUKBB data were obtained under the project #18219Some aspects of this work have been previously presented at The Challenge of Chronic Pain: From Genomics to Therapy in UK and first 1st Danish International Conference on Personalised Medicine in Denmark.

Natural Products from Brazilian Biodiversity Explored as Anti-EBV Drug Candidates: In-Silico Database Mining, Docking Computations, Molecular Dynamics and DFT Calculations

A DNA tumor virus called Epstein–Barr virus (EBV) is the cause of 1–2% of human cancers. EBV-associated carcinogenesis is caused by a persistent latent infection. The shortage of antiviral medications or vaccinations to control the virus led to a significant percentage of critically sickness individuals needing to be hospitalized. In the absence of an effective vaccine and approved drug, there is an immediate need for treatments that can combat EBV infection. Epstein–Barr nuclear antigen 1 (EBNA1) is continually expressed in all malignancies linked to EBV; it is a desirable target for curative interference. Herein, natural product compounds from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database were mined to identify potent EBNA1 inhibitors. The performance of the molecular docking technique was initially assessed in expecting the ligand-target binding pose according to the available experimental data. On the basis of the estimated docking protocol, the NuBBE database was virtually screened toward the EBNA1 protein, and the natural compounds with binding scores less than KWG (calc. -7.8 kcal/mol) were subjected to molecular dynamics (MD) simulations followed by binding energy ([Formula: see text] calculation using MM/GBSA approach. Based on binding energy computations, NuBBE1460 revealed superior [Formula: see text] with a value of −36.2 kcal/mol, compared to KWG (calc. -32.4 kcal/mol). Post-MD analyses displayed a high steadiness of NuBBE1460 within the EBNA1 protein binding pocket. Furthermore, the physicochemical, pharmacokinetic and toxicity features of the identified compound were predicted, demonstrating high degrees of its oral bioavailability. The energetical and geometrical properties of NuBBE1460 were calculated using the DFT method. Conclusively, this study offers NuBBE1460 obtained from natural sources as a lead EBNA1 inhibitor for future investigation and development as a therapeutic for EBV.

The Impact of Environmental Factors on the Development of Autoimmune Thyroiditis-Review.

Autoimmune thyroiditis (Hashimoto's thyroiditis) is the most common autoimmune disease. It most often manifests itself as hypothyroidism but may also present with euthyroidism or even hyperthyroidism. The etiopathogenesis of autoimmune thyroiditis is still unclear. However, in addition to genetic and epigenetic factors, many environmental factors are known to increase the risk of developing AIT. In this review, we aimed to collect and analyze data connected with environmental factors and autoimmune thyroiditis development. Our review indicates iodine intake, vitamin D deficiency, selenium deficiency, viral infections caused by Epstein-Barr Virus (EBV), Human parvovirus B19 (PVB19), Human herpesvirus 6A (HHV-6A) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bacterial infection caused by Helicobacter pylori, microbiome disruption, medications such as interferon-alpha and tyrosine kinase inhibitors, as well as stress, climate, and smoking can influence the risk of the occurrence of autoimmune thyroiditis. Having knowledge of risk factors allows for making changes to one's diet and lifestyle that will reduce the risk of developing the disease and alleviate the course of autoimmune thyroiditis.

Early predictors of Epstein-Barr virus infection in patients with severe fever with thrombocytopenia syndrome

BackgroundEpstein-Barr virus (EBV) can be reactivated and proliferated with fatal outcome in immuno-compromised people, but the clinical consequences of EBV infection in patients with severe fever with thrombocytopenia syndrome (SFTS) remain uncertain. In this study, we investigated the infection rate, the influence and the early predictors of EBV infection in SFTS patients.MethodsIn this retrospective study, SFTS patients who were treated in the First Affiliated Hospital of Nanjing Medical University from May 2011 to August 2021 were enrolled and divided into infected and non-infected groups. We compared the demographic characteristics, clinical manifestations and signs, laboratory tests and prognosis, and explored the risk factors of EBV infection by receiver operating characteristic (ROC) curve and logistic regression.ResultsA total of 120 hospitalized SFTS patients with EBV-DNA testing were enrolled in this study. Patients with EBV infection had statistically significant higher mortality rate (32.0% vs. 11.43%, P = 0.005). Compared with the non-infected group, the EBV-infected group had higher levels of C-reactive protein (CRP), creatine-kinase (CK), fasting blood glucose (FBG), blood urea nitrogen (BUN), D-dimer, and CD56+ cell counts, lower levels of immunoglobulin G (IgG), IgM, complement 3 (C3), and C4. The proportion of patients with age ≥ 60 years and ferritin > 1500.0 ng/ml in the EBV-infected group was significantly higher than that in the non-infected group. The results of ROC analysis showed that the cut-off values of CRP, IgG, C3, C4, and CD56+ cell counts to predict EBV infection were 13.2 mg/l, 12.5 g/l, 1.1 g/l, 0.6 g/l, 0.3 g/l, and 94.0 cells/µl. Multivariable logistic analysis showed that age ≥ 60 years old, CRP > 13.2 mg/l, BUN > 5.4 mmol/l, ferritin > 1500.0 ng/ml, IgG < 12.5 g/l, IgM < 1.1 g/l, C4 < 0.3 g/l, and CD56+ cell counts > 94.0 cells/µl were the independent risk factors of EBV infection in SFTS patients.ConclusionsSFTS combined with EBV infection is associated with high morbidity and mortality. It is necessary to strengthen screening for EBV infection and its early predictive markers after admission in SFTS patients.

Features of the neutrophil granulocyte phenotype in children with infectious mononucleosis

The course of infectious diseases caused by viruses, and their common outcome is determined by the activity of the inflammatory reaction which occurs both at the local and systemic levels. However, the features of neutrophil functions during inflammatory reaction are virtually unknown in the patients with infectious mononucleosis (IM), caused by Epstein–Barr virus (EBV). Hence, the aim of our study was to evaluate some characteristics of phenotypic spectrum of blood neutrophils in children with IM. Patients and methods. We examined 84 children aged 3 to 11 years with EBV infection with moderate or severe clinical course of the disease. All patients exhibited a positive test for EBV DNA in blood lymphocytes and appropriate serological markers of acute EBV infection. The control group consisted of 40 conditionally healthy children at the similar age range. The study of neutrophil phenotype was carried out by flow cytometry using direct immunofluorescence of whole peripheral blood samples. A study of the neutrophil phenotype with a combination of two functional antigens (CD64 and CD32) has revealed that in children with IM, regardless of age, the main fraction of blood neutrophils are double-negative cells, whereas in healthy children it consists of CD64-CD32+ neutrophils. The main fraction of neutrophils in the paired combination of CD64 and CD11b antigens in sick children aged 3-6 and 7-11 years was similar to the healthy controls (CD64-CD11b+), but with a change in the content of minor cell fractions. The number of CD64-CD15+ neutrophils (main fraction of cells in healthy children) proved to be significantly reduced in the IM patients of both age groups. However, we have revealed a marked increase in the level of double-negative cells for the CD64 and CD15 antigens. At the same time, the content of double-negative neutrophils for these markers was also increased in IM children of both age groups. The cells with CD11b-CD15+ and CD11b+CD15+ phenotypes comprised the main fractions in IM, as studied by a paired combination of CD11b and CD15 antigens; in healthy children – only CD11b+CD15+ neutrophils are detected. The phenotypic changes of neutrophils during IM suggest a decreased migratory ability of cells with high activity of proinflammatory functions. The established ontogenetic features of the neutrophil phenotype are significantly changed in the children with IM, probably, due to specific immunopathogenesis of the viral infection. The detected changes in phenotypic composition of neutrophils associated with IM may be caused both by the features of protective reaction of innate immune cells and pathogenic effects of the virus itself upon blood neutrophils.

Quantitatively assessed blood leukocyte Epstein–Barr virus in adult HIV-infected patients

Coinfection with the human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV) represents a current biomedical problem. The purpose of the study was to evaluate blood leukocyte EBV detection rate and viral load in adult HIV-infected patients. Materials and methods. There were examined blood leukocytes collected from 138 HIV(+) and 68 HIV(–) individuals aged 20–69 years. Statistical analysis was carried out differentiated according to the stages of HIV infection, the CD4+ T-lymphocyte count, and adherence to antiretroviral therapy. Results. It was shown that EBV DNA was detected significantly more often in HIV(+) vs HIV(–) individuals (70.3±3.9% and 48.5±6.1%, p = 0.008), with EBV viral load comprising 18 [5; 139] versus 2 [1; 3] copies/105 cells (р 0.001), respectively. It has been shown that the group of HIV(+) patients is heterogeneous in the frequency of EBV detection and viral load, with the peak EBV frequency (86.7±6.2%) and DNA (121 [34; 252] copies/105 cells) level observed in “naive” patients with severe immunodeficiency. Among “experienced” patients receiving therapy, the relative risk of detecting EBV DNA with low treatment adherence was significantly higher compared to those who developed high adherence (р 0.05). When the HIV viral load reached undetectable level, EBV DNA concentration was significantly lower where HIV RNA was detectable (1 [0; 8] versus 15 [1; 162] copies/105 cells, р 0.001). Detection of EBV DNA is associated with higher HIV viral load level and lower CD4+ T-lymphocyte count compared to patients with undetected EBV DNA. A relationship has been established between the CD4+ T-lymphocyte count in HIV(+) patients and the likelihood of active EBV infection. A threshold cut-off of 200 cells/μl was determined. CD4+ T-lymphocyte count 200 cells/μl vs ≥ 200 cells/μl (р 0.001) is associated with a 3.3-fold higher risk of detecting active EBV infection. Conclusion. It is necessary to continue interdisciplinary research to improve early diagnostics of EBV-associated diseases in HIV-infected individuals.

Aquaporin-3 is down-regulated by LMP1 in nasopharyngeal carcinoma cells to regulate cell migration and affect EBV latent infection.

Epstein-Barr virus (EBV) infection has a strong correlation with the development of nasopharyngeal carcinoma (NPC). Aquaporin 3 (AQP3), a member of the aquaporin family, plays an important role in tumor development, especially in epithelial-mesenchymal transition. In this study, the expression of AQP3 in EBV-positive NPC cells was significantly lower than that in EBV-negative NPC cells. Western blot and qRT-PCR analysis showed that LMP1 down-regulated the expression of AQP3 by activating the ERK pathway. Cell biology experiments have confirmed that AQP3 affects the development of tumor by promoting cell migration and proliferation in NPC cells. In addition, AQP3 can promote the lysis of EBV in EBV-positive NPC cells. The inhibition of AQP3 expression by EBV through LMP1 may be one of the mechanisms by which EBV maintains latent infection-induced tumor progression.

Rash decisions: Unmasking a risk phenotype in adults with persistent delayed penicillin allergy sensitized during historic infection with Epstein-Barr virus

BackgroundPenicillin-associated exanthems in the setting of infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) are often viewed as a transient event, and not a true allergy. Recent evidence challenges this and suggest a notable subset of patients retain penicillin hypersensitivity. ObjectiveWe investigated the occurrence and predictors of persistent adulthood hypersensitivity in those with a penicillin-associated rash occurring in the setting of EBV infection. MethodRetrospective analysis of patients referred for penicillin allergy testing to an Australian tertiary hospital captured from 2015 to 2023 was carried out. ResultsOf 2,066 patients, 23 (1%) had a penicillin-associated rash during an historic EBV infection; 16 (70%) female, median 18 years (interquartile range [IQR] 16-20) at index reaction, median 38 years (IQR 33.5-57) when allergy tested. Skin-prick and delayed-intradermal testing (D-IDT) to a penicillin panel were performed and oral provocation challenge in those testing negative. Persistent sensitisation was shown in 6/23 (26%); 4/6 (67%) positive D-IDT, 3/6 (50%) positive oral challenge. Notably, 5/6 (83%) had a severe maculopapular exanthem (sMPE) with facial swelling, including 2/6 (33%) with probable drug reaction with eosinophilia and systemic symptoms (DRESS) during the index reaction, compared with 0/17 (0%) in patients tolerating penicillin on re-exposure. ConclusionThis study highlights the requirement of allergy testing in adult patients reporting a penicillin-associated sMPE in the setting of EBV, even if occurring during childhood or adolescence.

Transplantation in adult patients with Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis: yes or no?

AbstractHemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by aberrant immunological activity with a dismal prognosis. Epstein-Barr virus (EBV)–associated HLH (EBV-HLH) is the most common type among adults. Patients with EBV infection to B cells could benefit from rituximab, whereas lethal outcomes may occur in patients with EBV infection to T cells, nature killer cells, or multilineages. The necessity of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with EBV-HLH remains controversial. A total of 356 adult patients with EBV-HLH entered this study. Eighty-eight received HSCT under medical recommendation. Four received salvage HSCT. The 5-year overall survival (OS) rate for patients who underwent HSCT was 48.7% (vs 16.2% in patients who did not undergo transplantation; P < .001). There was no difference in OS between patients who received transplantation at first complete response (CR1) and those at first partial response (PR1) nor between patients at CR1 and CR2. Patients who received transplantation at PR2 had inferior survival. The rate of reaching CR2 was significantly higher in patients with CR1 than PR1 (P = .014). Higher soluble CD25 levels, higher EBV-DNA loads in plasma after HSCT, poorer remission status, more advanced acute graft-versus-host disease (GVHD), and the absence of localized chronic GVHD were associated with inferior prognosis (P < .05). HSCT improved the survival of adult EBV-HLH significantly. For patients who achieved PR after initial treatment, HSCT was recommended. A wait-and-see strategy could be adopted for patients who achieved CR after initial treatment but with the risk of failing to achieve CR2.

New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis.

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as "progression independent of relapse activity" and "silent progression," now thought to take hold very early in the course, together argue that an underlying "cytodegenerative" process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein-Barr virus and B cells in this process is also discussed.

Stearoyl-CoA desaturase 1 is targeted by EBV-encoded miR-BART20-5p and regulates cell autophagy, proliferation, and migration in EBV-associated gastric cancer.

Epstein-Barr virus (EBV) is the first human oncogenic virus known to express microRNAs (miRNAs), which are closely associated with the development of various tumors, including nasopharyngeal and gastric cancers. Stearoyl-CoA Desaturase 1 (SCD1) is a key enzyme in fatty acid synthesis, highly expressed in numerous tumors, promoting tumor growth and metastasis, making it a potential therapeutic target. In this study, we found that SCD1 expression in EBV-associated gastric cancer (EBVaGC) was significantly lower than in EBV-negative gastric cancer (EBVnGC) at both cellular and tissue levels. In addition, EBV-miR-BART20-5p targets the 3'-UTR of SCD1, downregulating its expression. Moreover, overexpression of SCD1 in EBVaGC cells promoted cell migration and proliferation while inhibiting autophagy. These results suggest that EBV-encoded miRNA-BART20-5p may contribute to EBVaGC progression by targeting SCD1.

The impact of CLDN18.2 expression on effector cells mediating antibody-dependent cellular cytotoxicity in gastric cancer

Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages—crucial effector cells of ADCC—in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein–Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC.

Comparative Study Analysis of Epstein-Barr Virus Infection: Tissue Versus Blood Samples in Patients With Prostatic Adenocarcinoma and Its Correlation With Clinicopathological Parameters.

Prostate cancer (PCa) is the most frequently diagnosed cancer and a leading cause of cancer-related mortality in men. The diagnosis and treatment of PCa carry considerable medical, psychological, and economic implications. Among the risk factors contributing to cancer, viral infections, notably Epstein-Barr virus (EBV), play a significant role. It is recognized as an oncogenic virus associated with various lymphomas, nasopharyngeal carcinomas, and breast cancer cases but its role in PCa remains unclear. This study aims to contrast the prevalence of EBV in blood and tissue samples of PCa patients and assess its correlation with tumor clinicopathological criteria. In this prospective study, 50 fresh biopsies and 50 blood samples were collected from patients with a confirmed diagnosis of PCa. EBV DNA was detected using polymerase chain reaction (PCR). A statistical analysis was then conducted to examine the correlation between EBV prevalence and PCa clinicopathological characteristics. EBV DNA was detected in 38% of PCa blood samples and 64% of PCa tissue samples, with a higher prevalence in tissue samples (p = 0.009). The statistical analysis revealed a significant correlation between EBV infection andpathological Gleason score (p = 0.041) in PCa tissue, as well as pathological T-stage (p = 0.02) in PCa blood. The results show that patients with PCa have higher levels of EBV in their tissues than in their blood, suggesting that EBV may play an important role in the etiology of PCa. This paves the way for further research into the function of EBV as a potential biomarker in the development and progression of prostate carcinoma in order to combatoncogenic viruses.

Effect of Plasma Epstein-Barr Virus Nucleic Acid Loads on the Clinical Features and Prognosis in Adult Secondary Hemophagocytic Lymphohistiocytosis

To investigate the effect of pre-treatment plasma Epstein-Barr virus (EBV) DNA copy number on the clinical features and prognosis of patients with adult secondary hemophagocytic lymphohistiocytosis(sHLH). The clinical characteristics, survival rate, and prognostic factors of 171 patients with adult sHLH treated at Jiangsu Province Hospital from June 2017 to January 2022 were retrospectively analyzed in this study. Patients were divided into three groups, including the EBV DNA-negative group(<5.0×102 copies/ml), lower EBV-DNA loads group(5.0×102-8.51×104 copies/ml), and higher EBV-DNA loads group(＞8.51×104 copies/ml), according to pre-treatment plasma EBV-DNA copy number. Cox regression model was established for screening prognostic factors. Adult sHLH survival prediction model was constructed and realized through the nomogram based on EBV-DNA load after adjusted the factors affecting survival of etiology and treatment strategy.Concordance index (C-index) and calibration curves were calculated to verify model predictive and discriminatory capacity. Among 171 adult sHLH patients, 84 patients were not infected with EBV (EBV DNA-negative group), and 87 with EBV (EBV DNA-positive group, 48 lower EBV-DNA loads group and 39 higher EBV-DNA loads group). Consistent elevations in the levels of liver enzymes (ALT and AST), LDH, TG, β 2-microglobulin and ferritin across the increasing of EBV-DNA load (all P <0.05), while the levels of fibrinogen decrease (P <0.001). The median follow-up time was 52 days (range 20-230 days), and 123 patients died. The overall survival (OS) rate of patients in EBV DNA-positive group was lower than that in EBV DNA-negative group (median OS: 40 days vs 118 days, P <0.001). Higher EBV-DNA loads had worse OS (median OS: 24 days vs 45 days vs 118 days, P <0.0001 for trend) compared to lower EBV-DNA loads and EBV DNA-negative group. Multivariate Cox analysis revealed that higher EBV-DNA loads (P =0.005), fibrinogen≤1.5 g/L (P ＝0.012), ferritin (P ＝0.041), associated lymphoma (P ＝0.002), and anti-tumor based strategy (P ＝0.001) were independent prognostic factors for OS. The C-indexes of 30 day, 90 days, 365 days survival rate were all greater than 0.8 of the nomogram model and calibration curves provided credibility to their predictive capability. Subgroup analysis showed that patients with higher EBV-DNA loads had a significantly worse prognosis in adult sHLH who were women, ferritin＞5 000 μg/L, β2-microglobulin＞7.4 mmol/L and regardless of age, etiologies, HScore points. The EBV-DNA load is a strong and independent predictor for survival in patients with sHLH. The prognostic nomogram based on EBV-DNA loads was dependable and provides a visual tool for evaluating the survival of adult sHLH.

Clinical Analysis of Epstein-Barr Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

To analyze the risk factors of Epstein-Barr virus (EBV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its impact on survival. The clinical data of 347 patients who underwent their first allo-HSCT in our hospital from January 2014 to June 2021 were retrospectively analyzed. Patients were divided into EBV (n =114) and Non-EBV (n =233) groups according to whether they were infected with EBV. The incidence of EBV infection after allo-HSCT was calculated, and the risk factors of EBV infection were analyzed. A total of 114(32.8%) patients presented EBV infection (all peripheral blood EBV-DNA were positive). EBV infection occurred in 88 patients within 100 days after transplantation, which accounted for 77.2% of all patients with EBV infection. 5 cases (1.44%) were confirmed as post-transplant lymphoproliferative disorder (PTLD). The median onset time of patients was 57(7-486) days after transplantation. Multivariate analysis showed that the use of ATG/ATG-F, occurrence of CMV viremia, and grade III-IV aGVHD were risk factors for EBV infection. Furthermore, compared to BUCY, the use of intensified preconditioning regimens containing FA/CA was significantly increased the risk of EBV infection. EBV infection is a common complication after allo-HSCT. Intensified preconditioning regimens, use of ATG/ATG-F, CMV viremia and grade III to IV aGVHD increase the risk of EBV infection after allo-HSCT.

Epstein-Barr Virus-Associated Smooth Muscle Tumor After Kidney Transplantation: A French Multicenter Retrospective Study.

Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.

Causal relationships of infection with Helicobacter pylori and herpesvirus on periodontitis: A Mendelian randomization study

BackgroundTo explore the causal association between Helicobacter pylori (H. pylori) infection, herpesvirus infection and periodontitis (PD) from a genetic perspective using Mendelian randomization (MR). MethodsThe PD data were derived from genome-wide association study (GWAS) from the Dental Endpoints (GLIDE) consortium, and the FinnGen Biobank provided data on H. pylori and herpesvirus infections. In addition, we examined GWAS data for subtypes of H. pylori and herpesvirus infection. Inverse variance weighting (IVW) was selected as a major analysis technique, and weighted median (WM), weighted model, simple model, and MR-Egger regression were added as supplementary methods. To verify the findings, the effects of pleiotropy and heterogeneity were assessed. ResultsGenetically predicted H. pylori infection (OR = 0.914, 95%CI = 0.693–1.205, P = 0.523), anti-H. pylori VacA (OR = 0.973, 95%CI = 0.895–1.057, P = 0.515), anti-H. pylori CagA (OR = 1.072, 95%CI = 0.986–1.164; P = 0.102), Epstein-Barr virus (EBV) infection (OR = 1.026, 95%CI = 0.940–1.120, P = 0.567), Herpes simplex virus (HSV) infection (OR = 0.962, 95%CI = 0.883–1.048, P = 0.372), cytomegalovirus (CMV) infection (OR = 1.025, 95%CI = 0.967–1.088, P = 0.415), EBV nuclear antigen-1 (EBNA1) (OR = 1.061, 95%CI = 0.930–1.209, P = 0.378), EBV virus capsid antigen (VCA) (OR = 1.043, 95CI% = 0.890–1.222, P = 0.603), HSV-1 (OR = 1.251, 95%CI = 0.782–2.001, P = 0.351), HSV-2 (OR = 1.020, 95%CI = 0.950–1.096, P = 0.585), CMV IgG (OR = 0.990, 95CI% = 0.882–1.111, P = 0.861) were not associated with PD, indicated that H. pylori and herpesvirus infection had no causal relationship to PD. Reverse studies also found no cause effect of PD on H. pylori or herpesvirus infection. The results of the sensitivity analysis suggested the robustness of the MR results. ConclusionThis study offered preliminary proof that H. pylori and herpesvirus infections were not causally linked to PD, and vice versa. However, more robust instrumental variables (IVs) and larger samples of GWAS data were necessary for further MR analysis.

Glutathione hybrid poly (beta-amino ester)-plasmid nanoparticles for enhancing gene delivery and biosafety

IntroductionCRISPR/Cas9 gene editing technology has significantly advanced gene therapy, with gene vectors being one of the key factors for its success. Poly (beta-amino ester) (PBAE), a distinguished non-viral cationic gene vector, is known to elevate intracellular reactive oxygen species (ROS) levels, which may cause cytotoxicity and, consequently, impact gene transfection efficacy (T.E.). ObjectivesTo develop a simple but efficient strategy to improve the gene delivery ability and biosafety of PBAE both in vivo and in vitro. MethodsWe used glutathione (GSH), a clinically utilized drug with capability to modulating intracellular ROS level, to prepare a hybrid system with PBAE-plasmid nanoparticles (NPs). This system was characterized by flow cytometry, RNA-seq, Polymerase Chain Reaction (PCR) and Sanger sequencing in vitro, and its safety and efficacy in vivo was evaluated by imaging, PCR, Sanger sequencing and histology analysis. ResultsThe particle size of GSH-PBAE-plasmid NPs were 168.31 nm with a ζ-potential of 15.21 mV. An enhancement in T.E. and gene editing efficiency, ranging from 10 % to 100 %, was observed compared to GSH-free PBAE-plasmid NPs in various cell lines. In vitro results proved that GSH-PBAE-plasmid NPs reduced intracellular ROS levels by 25 %–40 %, decreased the total number of upregulated/downregulated genes from 4,952 to 789, and significantly avoided the disturbance in gene expression related to cellular oxidative stress-response and cell growth regulation signaling pathway compared to PBAE-plasmid NPs. They also demonstrated lower impact on the cell cycle, slighter hemolysis, and higher cell viability after gene transfection. Furthermore, GSH hybrid PBAE-plasmid NPs exhibited superior safety and improved tumor suppression ability in an Epstein–Barr virus (EBV)-infected murine tumor model, via targeting cleavage the EBV related oncogene by delivering CRISPR/Cas9 gene editing system and down-regulating the expression levels. This simple but effective strategy is expected to promote clinical applications of non-viral vector gene delivery.

Epstein-Barr virus noncoding RNA EBER1 promotes the expression of a ribosomal protein paralog to boost oxidative phosphorylation.

Epstein-Barr virus (EBV) is a highly successful pathogen that infects ~95% of the adult population and is associated with diverse cancers and autoimmune diseases. The most abundant viral factor in latently infected cells is not a protein but a noncoding RNA called EBV-encoded RNA 1 (EBER1). Even though EBER1 is highly abundant and was discovered over forty years ago, the function of EBER1 has remained elusive. EBER1 interacts with the ribosomal protein L22, which normally suppresses the expression of its paralog L22-like 1 (L22L1). Here we show that when L22 binds EBER1, it cannot suppress L22L1, resulting in L22L1 being expressed and incorporated into ribosomes. We further show that L22L1-containing ribosomes preferentially translate mRNAs involved in the oxidative phosphorylation pathway. Moreover, upregulation of L22L1 is indispensable for growth transformation and immortalization of resting B cells upon EBV infection. Taken together, our results suggest that the function of EBER1 is to modulate host gene expression at the translational level, thus bypassing the need for dysregulating host gene transcription.

COVID-19 and Carcinogenesis: Exploring the Hidden Links.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has been studied predominantly in terms of its immediate respiratory and systemic effects. However, emerging evidence suggests possible long-term effects, including its role in carcinogenesis. This comprehensive review explores the complex relationship between COVID-19 and cancer development, focusing on immune dysregulation, chronic inflammation, genetic and epigenetic alterations, and the impact of therapeutic interventions. We also focused on the molecular mechanisms by which SARS-CoV-2 may facilitate cancer progression, including the roles of angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and FURIN. Additionally, we examined the possible carcinogenic effects of long-term COVID-19 treatments and the interaction between co-infections and cancer risk. Our findings highlight the need for increased cancer surveillance in COVID-19 survivors. In the post-COVID-19 period, it can be thought that inflammation associated with excessive cytokine release, especially interleukin-6, genetic and epigenetic changes, and co-infections with oncogenic viruses such as Epstein-Barr virus or human papillomavirus may be effective in the development and progression of cancer. Further research is needed to explain the mechanisms underlying this relationship.