The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection

AbstractHistone modifier lysine (K)-specific demethylase 2B(KDM2B) plays a role in hematopoietic cells differentiation and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that KDM2B gene is differentially methylated in cell lines derived from the Epstein-Barr virus (EBV) associated endemic Burkitt’s lymphomas (eBL) compared to EBV negative sporadic BL cells. However, whether KDM2B plays a role in eBL development has never been previously demonstrated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here we investigated whether EBV would alter KDM2B levels to enable its life cycle and promote B-cells transformation. We show that infection of B-cells with EBV leads to down-regulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to KDM2B gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV infected B-cells, we were able to show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B-cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis.IMPORTANCE. In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared to the sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared to sporadic Burkitt lymphomas cell lines, we identified several differential methylated genomic positions in proximity of genes with a potential role in cancer, among them the KDM2B gene. KDM2B encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has never been investigated before. In this study we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cells genes expression, thus highlighting a novel interaction between the virus and the cellular epigenome.

Download Full-text

PREVALENCE OF POLYMORPHISM OF THE TLR-9 TYPE GENE IN PATIENTS WITH CHRONIC EPSTEIN-BARR VIRUS INFECTION

The Journal of V. N. Karazin Kharkiv National University, Series "Medicine" ◽

10.26565/2313-6693-2018-35-06 ◽

2018 ◽

Keyword(s):

Virus Infection ◽

Frequency Distribution ◽

Genetic Background ◽

Epstein Barr Virus ◽

Risk Groups ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

The prevalence of polymorphism -1486T/C of the TLR-9 gene was studied in 44 patients with chronic Epstein-Barr virus infection (CEBV). The control group for the study of the polymorphisms prevalence of -1486T/C of the TLR-9 gene was 40 healthy donors. Three main genotypes of -1486T/C of the TLR-9 gene were identified based on the obtained results – TT, TC, CC. Investigation of the occurrence frequency of individual genotypes revealed the dominance of the TC genotype, compared with the homozygous TT and CC genotypes. The study of -1486T/C of the TLR-9 gene polymorphism frequency distribution for different genotypes demonstrated the specificity of changes in the TC genotype in patients with CEBV and the absence of such for the TT and CC genotypes. These results confirm the important role of the TLR-mediated signaling in the pathogenesis of the disease, which is necessary to determine the genetic background associated with the course of the disease and its possible consequences. These are the aspects that will further enable the identification of risk groups among such patients and provide timely therapy. The analysis of the results of the -1486T/C polymorphism of the TLR-9 gene revealed three main genotypes –TT, TC, CC. Investigation of the occurrence frequency of individual genotypes revealed the dominance of the genotype TC, compared with the homozygous genotypes of TT and CC. The study of frequency distribution of the polymorphism -1486T/C of TLR-9 for different genotypes demonstrated the specificity of changes in the TC genotype and the absence of suchin the TT and CC genotypes in patients with CEBV.Our study for the purpose of determining the 1486T/C polymorphism of the TLR-9, that is associated with chronic forms of CEBV infection, confirms the important role of TLR-mediated signaling in the pathogenesis of this disease, which is necessary to determine the genetic background associated with the course of the disease and possible consequences of CEBV. These aspects will further enable the identification of risk groups among such patients and provide timely therapy.Analysis of the results allowed establishing the following:1. The 1486T/C polymorphism of the TLR-9 gene is significantly more frequent in patients with CEBV than in the control.2. The frequency distribution of the -1486T/C polymorphism ofthe TLR-9 gene allowed the establishment of the association of the genotype TC with chronic forms of the EBV infection, which is very specific for this group of patients.

Download Full-text