A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-04-04
DOI
https://doi.org/10.1073/pnas.2418783122
Citations
14
Primary Topic
Multiple Sclerosis Research Studies
Type
article
Field-Weighted Citation Impact
20.60

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A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis

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Proceedings of the National Academy of Sciences
Multiple Sclerosis Research Studies
20.60
article

A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis

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article en
14 citations

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.

Proceedings of the National Academy of SciencesVol. 122(14)
University of Rome Tor Vergata (IT), University of Verona (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Harvard University (US), University of Massachusetts Chan Medical School (US), University of Cagliari (IT), University of California, San Francisco (US), Cornell University (US), Istituto Neurologico Mediterraneo (IT), Massachusetts General Hospital (US), ASL Roma (IT), Neuroscience Institute (IT), Istituto per le Tecnologie Didattiche (IT), Institute for Experimental Endocrinology and Oncology (IT), Ospedale Policlinico San Martino (IT), Fondazione Santa Lucia (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institute of Biomedical Technologies (IT), Ospedale San Luigi Gonzaga (IT), Piedmont University (US), Weill Cornell Medicine (US), Imperial College London (GB), University of Turin (IT), Massachusetts Institute of Technology (US), Sapienza University of Rome (IT)
National Multiple Sclerosis Society, Sanofi, Biogen, Teva Pharmaceutical Industries, Alexion Pharmaceuticals, Celgene, Fondazione Italiana Sclerosi Multipla, Wellcome Trust, GW Pharmaceuticals, Mylan, Multiple Sclerosis Society, Ministero della Salute, Sapienza Università di Roma, Allergan, Sanofi Genzyme
Good health and well-being
Openalex Percentile: Top 0%
Multiple Sclerosis Research Studies
20.60
DOIOpen Access PDFOpenAlex
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