The interaction between Epstein-Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease, characterised by the demyelination of neurons in the central nervous system. Whilst it is unclear what precisely leads to MS, it is believed that genetic predisposition combined with environmental factors plays a pivotal role. It is estimated that close to half the disease risk is determined by genetic factors. However, the risk of developing MS cannot be attributed to genetic factors alone, and environmental factors are likely to play a significant role by themselves or in concert with host genetics. Epstein-Barr virus (EBV) infection is the strongest known environmental risk factor for MS. There has been increasing evidence that leaves little doubt that EBV is necessary, but not sufficient, for developing MS. One plausible explanation is EBV may alter the host immune response in the presence of MS risk alleles and this contributes to the pathogenesis of MS. In this review, we discuss recent findings regarding how EBV infection may contribute to MS pathogenesis via interactions with genetic risk loci and discuss possible therapeutic interventions.

Keywords: EBNA2; EBV; GWAS; RNA therapeutics targeting EBV; multiple sclerosis; risk genetic variation.

Figure 1

Interaction between EBV and MS risk loci in the latency III infected B cell. Epstein–Barr virus (EBV) dysregulates the B‐cell transcriptome, including genes proximal to MS risk loci (MS risk genes), either directly or indirectly, which may contribute to MS pathogenesis. EBNA2, an EBV encoded transactivator protein specific to latency III, regulates the expression of MS risk genes by preferentially binding to the protective or risk alleles at the respective MS risk loci. This preferential binding could alter the effect of risk alleles on gene expression. In the case of ZC3HAV1, the MS risk allele reduces expression. This may happen through EBV elements, or as a consequence of EBV‐related molecular processes in the infected B cell context. The net effect of these interactions may alter molecular pathways in B cells resulting in less control of EBV infection via a reduction in anti‐viral responses and apoptosis as well as an increase in cell proliferation. Further experimental validation is needed to prove this postulated model at the physiological level. The image was created using BioRender.com, under the agreement number OB24ZS37BU.