A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis
Author(s)
Type
Journal Article
Abstract
Recent sero-epidemiological studies have strengthened the hypothesis that Epstein–Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV–host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.
Date Issued
2025-04-08
Date Acceptance
2025-01-27
Citation
Proceedings of the National Academy of Sciences, 2025, 122 (14)
ISSN
0027-8424
Publisher
Proceedings of the National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences
Volume
122
Issue
14
Copyright Statement
© 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40184175
Subjects
Epstein–Barr virus
autoimmunity
multiple sclerosis
Multiple Sclerosis
Humans
Herpesvirus 4, Human
Epstein-Barr Virus Nuclear Antigens
Epstein-Barr Virus Infections
CD40 Antigens
Brain
Host-Pathogen Interactions
Viral Proteins
RNA Polymerase II
Genetic Predisposition to Disease
Publication Status
Published
Coverage Spatial
United States
Article Number
e2418783122
Date Publish Online
2025-04-04