The Interactions of Epstein-Barr virus and Genetic Risk Factors in Multiple Sclerosis

Abstract

EBV is considered necessary but not sufficient for MS development. Genome-wide association studies have identified over 200 risk loci for MS, which indicate the importance of the immune system in susceptibility, but not the precise role. Variable response to EBV infection may underpin, or at least contribute, to MS risk. Recent evidence from our group and others from studies of the genetic risk factors has implicated the EBV transactivating protein EBNA2 and the growth phase it regulates, EBV latency III, in MS pathogenesis. This thesis investigated the potential EBV latency III role in MS development by utilising in silico approaches followed by functional studies using EBV-infected B cells, lymphoblastoid cell lines (LCLs). Specifically, we investigated whether EBNA2 regulates MS risk genes in a genotype-dependent manner and investigated the viability of directly targeting EBNA2 to control EBV. We further sought to determine whether oestrogen signalling in EBV-infected B cells could contribute to MS susceptibility and the gender effect in MS by altering MS risk gene expression and EBV viral functions. The first study of this thesis provides confirmation that EBNA2 binds to several MS risk loci in EBV infected B cells in a risk allele-dependent manner to regulate several EBNA2-associated MS risk genes. The second study investigates a novel approach to target EBV and EBNA2-associated diseases including MS, using modified anti-EBNA2 ASOs, which has important translational implications. Lastly, the third study demonstrates that oestrogen signalling alters both MS risk gene and EBV functions, supporting the notion that sex differences in host response to EBV infection could contribute to sex differences in MS. Overall, the studies in this thesis indicate mechanisms by which EBV may influence MS pathogenesis by interacting with MS genetic risk loci, and consequently provide new approaches for the potential targeting of EBV in MS therapy.