Defining the Role of Epstein-Barr Virus in Multiple Sclerosis

Project Summary/Abstract Multiple Sclerosis (MS) is the most common cause of non-traumatic disability in young adults affecting approximately one million individuals only in the United States. The pathophysiology of MS remains unclear. Infection with the Epstein-Barr Virus (EBV) is epidemiologically a pre- requisite for developing MS, as essentially all MS patients become infected with EBV before the onset of the disease. The Robinson lab at Stanford recently identified molecular mimicry between the EBV transcription factor EBNA1 and the glial cellular adhesion molecule GlialCAM in 20-25% of MS patients, which is likely a critical mechanism underlying the development of MS in this subset of patients. The proposed project will investigate the differences (presence/absence and the levels) in antibodies reactive to different EBV proteins with the potential for immunogenicity, using large patient cohorts. This study also aims to define the role of EBV reactivation and anti- EBV antibodies in relapse and progression of MS as well as response to treatment. The detailed education and training plan for this K23 Mentored Patient-Oriented Research Career Development Award will give the candidate, Dr. Sattarnezhad, the necessary skills to reach this goal by confirming three specific Aims. Aim 1 will characterize MS cohorts using proteomic analysis of the anti-EBV antibodies and neurodegenerative markers to investigate the role of EBV molecular mimicry in MS etiopathogenesis; Aim 2 will define the role of EBV reactivation in the disease activity in MS patients; and Aim 3 will perform integrated informatics analysis of the finding from Aims 1 and 2 to investigate the association between anti-EBV antibody levels with genetic, clinical, and imaging data of MS patients. Success of the proposed studies would elucidate the role of EBV in MS, which will transform our understanding of MS and can lead to fundamental therapies for the treatment of MS. The proposed career development plan will also provide Dr. Sattarnezhad with the support and training to become an independent clinician-scientist in neuroimmunology.