Epstein-Barr Virus-Driven B-Cell Inflammation and CNS Trafficking in MS
Abstract
Multiple sclerosis (MS) is the most prevalent demyelinating, autoimmune disorder of the central nervous system (CNS) and the most common disabling neurologic disease of young people, affecting an estimated 1,000,000 in the United States. The causes of MS are complex and multifactorial with genetic and environmental factors contributing collectively to MS susceptibility. Compelling new evidence indicates that Epstein-Barr virus (EBV) is an essential trigger and causative factor in all forms of MS. The association between EBV and MS is supported by numerous studies. Despite the preponderance of evidence implicating EBV in the development and progression of MS, the precise mechanisms that enable EBV-infected B cells to cause autoimmunity in the CNS are unknown. EBV is a ubiquitous human herpesvirus that normally establishes a stable latent infection in long-lived B lymphocytes. Our preliminary data suggests that the EBV latency is unstable in MS patients leading to the formation of highly reactive and inflammatory B cells that can migrate to the CNS to cause autoimmunity. At present, there are no U.S. Food and Drug Administration-approved drugs or vaccines that prevent EBV infection or treat EBV-infected B cells. Moreover, there are limited animal models to test the efficacy of new therapies that target EBV-infected B cells. This proposal aims to address these unmet medical needs. Specifically, we will use MS patient-derived EBV-infected B cells to identify the viral and host factors that give rise to pathogenic B cell inflammation and entry into the CNS. We have developed a novel mouse model that enables us to measure EBV-infected B cell movement into the CNS and determine their effects on neuronal health related to MS pathology. We have also developed a new small molecule inhibitor of EBNA1, the central regulator of EBV latency, to eliminate EBV latent infection in B lymphocytes. This new drug candidate will be tested for its ability to selectively block EBV-infected B cell inflammation and neuroinvasion associated with MS. This study will address the Focus Area Factors Contributing to Multiple Sclerosis Etiology, Prodrome, Onset, and Disease Course. This project is relevant to this Focus Area because it will increase our understanding of how EBV drives the development of inflammatory, pathogenic B cells in the CNS, identify specific genes and new drug targets responsible for EBV-infected B cell autoimmunity and neuropathology, and enable the testing of new small molecule inhibitors to EBNA1 in a newly developed animal model that recapitulates EBV-infected B cell involvement and pathogenesis in the CNS. The deliverables of this study are: (1) increase knowledge of underlying mechanisms connecting EBV infection to MS pathogenesis; (2) identify specific genes and targets for new therapeutic intervention; (3) test new small molecule inhibitors of EBV latent infection as viral-specific therapy to treat MS; and (4) develop a new mouse model to test the efficacy of EBV selective therapies on pathogenic B cells in the CNS. Importantly, an outcome of this work could be the development of a new therapy to selectively treat EBV-infected B cells rather than total B cell depletion or ablation therapies that are presently the most effective treatments for MS. The potential to avoid B cell immunodepletion by selectively targeting only EBV-infected B cells and/or their selective pathways of inflammation or CNS trafficking will provide a significant benefit to MS patients. In a Phase I clinical trial, our EBNA1 inhibitor has proved safe for daily use and could be available for testing in MS patients in the near future. Therefore, we believe that our EBNA1 inhibitor will have the potential to provide greater selectivity, reduce off-target complications, and treat a primary cause of B cell dysfunction triggering MS. These studies therefore have potential to meaningfully improve patient quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311049
Entities
People
- Paul Lieberman
Organizations
- United States Army
- Wistar Institute