Identification of multiple sclerosis-related genes regulated by EBV-encoded microRNAs in B cells

Abstract

Background: Multiple sclerosis (MS) is driven by the interaction between genetic susceptibility and environmental triggers, particularly to Epstein-Barr virus (EBV) infection. EBV-encoded microRNAs (miRNAs) are abundantly expressed in all stages of EBV infection and latency, which can target both viral and host cellular mRNAs, allowing EBV-infected B cells to evade the host immune response. However, it remains a big gap to understand the roles of EBV miRNAs and their target genes in MS pathogenesis.Methods: We investigated the correlation between MS-related viruses infection and MS risk quantitatively by systematic analysis. All MS-related genes in B cells were obtained by integrating MS susceptibility genes and differentially expressed genes from B cells. In comparison with differentially expressed genes from B cells after EBV infection in vitro, we con rmed EBV-regulated, MS-related genes. Subsequently, we obtained target EBV miRNAs which can regulate these genes from several online databases. By constructing pathway-pathway, pathway-gene and protein-protein interaction networks, we further screened out MS-related genes and risk pathways regulated by EBV miRNAs. Finally, we identi ed target EBV miRNAs may directly regulate MS-related genes through bioinformatic prediction and experimental validation.Results: EBV infection showed the strongest correlation with MS risk. A total of 873 MS-related genes and 52 risk pathways in B cells were obtained. We then identi ed 150 MS-related genes and 18 associated risk pathways that EBV was involved in. In addition, 42 human target genes regulated by 36 EBV miRNAs overlapped with EBV-regulated, MS-related genes. Finally, 15 target EBV miRNAs and their regulated, 6 MS-related genes (MALT1, BCL10, IFNGR2, STAT3, CDK6 and FOXP1) have been con rmed as crucial pathogenic molecules, which could promote the initiation and development of MS through NF-kappa B (MALT1 and BCL10) and PD-L1/PD-1 (IFNGR2 and STAT3) pathways. Surprisingly, ebv-miR-BHRF1-2-5p directly targeting MALT1 was con rmed by our experiments, and FOXP1 was identi ed as a target gene of ebv-miR-BART11.Conclusions: This work identi ed the target EBV miRNAs and their regulated, MS-related genes and risk pathways, which may provide a novel insight into discovering diagnostic biomarkers and therapeutic targets for MS.

Co-occurrence of myasthenia gravis and demyelinating diseases of the central nervous system: A case report and review

“…Whereas recent studies demonstrated that the interplay between T and B cells in immune responses participate in the pathogenesis and progression in MS [8] and NMOSD [7]. Many studies have proposed that humoral immune-mediated pathogenesis in MS, for the reasons that the OCB in the CSF, existence of B cell-rich aggregates in the meninges, and effective treatment of CD19/20monoclonals depleting B cells in patients [8,10].Study suggested that CD72 acts as an inhibitory co-receptor of B cells in MG [11],and finding was supporting the hypothesis of B cell activation in the antibody-mediated process of MS [11][12][13].Although MS is primarily mediated by T lymphocytes, there are some evidence that B cells and self-reactive antibodies play a role in the pathogenesis of MS as well [14]. The enhanced un-derstanding of T cell and B cell surface receptors and genes that are involved in the pathogenesis of MG and MS, needs further studies and clinical trials for developing more effective treatment options.…”

Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers

“…Significantly, such regulators have been recently linked to the pathogenesis of MS. In one study, seven MS susceptibility genes were found to be up-regulated by at least fifteen EBV-derived microRNAs [ 68 ]. All previous findings at the genomic level point to another critical link between EBV infection and the pathogenesis of MS aside from the classic hypothesis [ 17 ].…”

A 4D transcriptomic map for the evolution of multiple sclerosis-like lesions in the marmoset brain

“…Moreover, intralesional WM-enriched ME group iii (ME19, 13, 8) and ME18 ( Fig2E ) are marked by genes that are primarily expressed by immune cells ( MMP9 , FBP1 , S100A12 , GPNMB , CXCR4 , FigS7A-B ). Interestingly, CXCR4 (a hub gene in MS-related pathways (54)) is pathogenically regulated by Epstein-Barr virus (EBV) infection of B cells (55), which is thought to be in the causal chain of MS (56). Genes involved in lipid storage/catabolism and macrophage differentiation/activation ( CD36 , SLC37A2 , MSR1 , NR1H3 , PLA2G7 ) are differentially enriched in intralesional WM and are primarily expressed by myeloid cells (microglia, monocytes, and macrophages) and γδT cells ( FigS7B ).…”