Insights into the role of Epstein-Barr virus infection in multiple sclerosis using a novel humanized mouse model of disease

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system without a clear cause. Epstein-Barr virus (EBV) is proposed to contribute to the pathogenesis of MS through unknown mechanisms. Evidence for a role of EBV infection in MS comes from both epidemiological and experimental studies, however, due to its narrow host tropism, there are currently few suitable animal models of MS that incorporate EBV infection. Recent advancements in humanized mouse modelling has enabled direct infection for the study of EBV-associated malignancies. We therefore chose to evaluate the role of EBV infection in humanized mice with experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. Immunocompromised mice were engrafted with peripheral blood mononuclear cells (PBMC) derived from individuals with relapsing MS (RRMS) or from matched healthy EBV seropositive or seronegative donors. We observed that HuPBMC mice induced with EAE developed ascending paralysis, weight loss and signs of discomfort consistent with classical EAE models. Further, HuPBMC EAE showed significant T cell infiltration of both the brain and spinal cord, notably of IFN gamma-expressing CD4 and CD8 T cells, resulting in spinal cord and cerebellar demyelination. HuPBMC EAE mice derived from EBV seropositive donors developed earlier disease onset with more severe clinical symptoms compared to EBV seronegative donor-derived mice. We also observed increase disease severity among mice derived from RRMS patients compared to healthy controls. With continued improvement and characterization of this novel humanized EAE model, additional environmental and genetic risk factors can be evaluated in a system with human immune-mediated pathology.