073 – Experimental investigation of the role of Epstein-Barr virus infection in a novel humanized mouse model of multiple sclerosis

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073 – Experimental investigation of the role of Epstein-Barr virus infection in a novel humanized mouse model of multiple sclerosis

Jessica R. Allanach (1) – Blair K. Hardman (1) – Isobel C. Mouat (1) – Naomi M. Fettig (1) – Yu Gu (1) – Virginie S. E. Jean-Baptiste (1) – Iryna Shanina (1) – Lisa C. Osborne (1) – Galina Vorobeychik (2, 3) – Marc S. Horwitz (1)
Department of Microbiology & Immunology, University of British Columbia, Vancouver BC, Canada (1) – Fraser Health Multiple Sclerosis Clinic, Burnaby BC, Canada (2) – Division of Neurology – Department of Medicine, University of British Columbia, Vancouver BC, Canada (3)


Epstein-Barr virus (EBV), a human herpesvirus that establishes latent infection in B cells, is proposed to contribute to the pathogenesis of multiple sclerosis (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. We have previously shown that latent infection of mice with the murine homologue of EBV, termed gammaherpesvirus-68, results in an altered immune response and severe clinical disease when mice are induced with experimental autoimmune encephalomyelitis (EAE), an MS-like disease in animals. Recent advancements in humanized mouse models has enabled direct infection of mice for the study of EBV-associated malignancies, including rheumatoid arthritis and systemic erythematosus lupus. We therefore chose to evaluate the role of EBV infection in humanized mice with EAE. In our studies, HuPBMC mice were first generated by engrafting immunocompromised mice with peripheral blood mononuclear cells (PBMC) derived from individuals with relapsing MS (RRMS) or from matched healthy EBV seropositive or seronegative donors. Once sufficiently reconstituted, HuPBMC mice were then induced with EAE. We observed that HuPBMC EAE mice 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 differences in EAE between HuPBMC mice derived from RRMS patients and healthy controls. Given that MS patients are majority EBV seropositive, we are quantifying the viral load and EBV-specific immune response of donors and respective HuPBMC EAE mice to evaluate this association with disease severity. 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. Moreover, immunomodulatory therapies could be tested in this personalized preclinical model to assess the efficacy and mechanism of treatments.