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

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.

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 confirmed 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 identified target EBV miRNAs which may directly regulate MS-related genes through bioinformatic prediction.

EBV infection showed the strongest correlation with MS risk. A total of 568 MS-related genes and 80 risk pathways in B cells were obtained. We then identified 112 MS-related genes and 18 associated risk pathways that EBV was involved in. In addition, 33 human target genes regulated by 33 EBV miRNAs overlapped with EBV-regulated, MS-related genes. Finally, 15 target EBV miRNAs and their regulated, 7 MS-related genes (MALT1, BCL10, IFNGR2, STAT3, CXCR4, PTK2B and FOXP1) have been confirmed 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 confirmed by our experiments, and FOXP1 was identified as a target gene of ebv-miR-BART11.

This work identified the target EBV miRNAs and their regulated, MS-related genes as well as risk pathways, which may provide a novel insight into discovering diagnostic biomarkers and therapeutic targets for MS.