Uncovering the Mechanisms Driving Virus-Induced Central Nervous System Disease.

• Applicant: Florian Kurschus, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544701159

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), affects 2.8 million people worldwide. As of now, there is no cure for this disease and the triggering factors remain unknown. Infection with the Epstein-Barr virus (EBV) has long been suspected as the causal link but strong empirical support has not been delivered. DISRUPT-MS aims to answer the question of how EBV causes MS. First, we want to establish the role of epitope spreading, that is the expansion of an immune response to new epitopes or antigens beyond the original target, and the EBI2 receptor, a key immune system modulator, in establishing and propagating autoimmunity using Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating model. Secondly, we will use a humanised mouse model (BRGST) to study the mechanisms of how EBV-infected MS patient-derived B cells induce disease in the CNS. Thirdly, we will investigate the disruption of epitope spreading in the TMEV and BRGST models using a synthetic EBI2 ligand analogue with enhanced half-live to inhibit epitope spreading and prevent demyelination in the CNS. Lastly, we will identify the factors which put certain individuals at increased risk of developing MS after EBV infection. Accomplishing these four steps will establish a causal link between virus infection, epitope spreading and CNS disease development and fill in the key knowledge gaps in our understanding of the fundamental pathophysiological mechanisms governing the development and progression of MS. Uncovering the mechanism of how virus infection leads to the development of chronic CNS disease has the potential to stimulate a shift in how autoimmune diseases are studied and understood. Utilising the new mechanism of inhibiting epitope spreading will lead to the development of curative therapies for MS and other autoimmune inflammatory diseases.

• DFG Programme: Research Grants
• International Connection: Poland
• Cooperation Partner: Professorin Dr. Aleksandra Rutkowska