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

Rosella Mechelli; Renato Umeton; Gianmarco Bellucci; Rachele Bigi; Virginia Rinaldi; Daniela F. Angelini; Gisella Guerrera; Francesca C. Pignalosa; Sara Ilari; Marco Patrone; Sundararajan Srinivasan; Gabriel Cerono; Silvia Romano; Maria C. Buscarinu; Serena Martire; Simona Malucchi; Doriana Landi; Lorena Lorefice; Raffaella Pizzolato Umeton; Eleni Anastasiadou; Pankaj Trivedi; Arianna Fornasiero; Michela Ferraldeschi; IMSGC WTCCC2; Alessia Di Sapio; Gerolama Marfia; Eleonora Cocco; Diego Centonze; Antonio Uccelli; Dario Di Silvestre; Pierluigi Mauri; Paola de Candia; Sandra D’Alfonso; Luca Battistini; Cinthia Farina; Roberta Magliozzi; Richard Reynolds; Sergio E. Baranzini; Giuseppe Matarese; Marco Salvetti; Giovanni Ristori

doi:10.1073/pnas.2418783122

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

Rosella Mechelli (Lead / Corresponding author), Renato Umeton, Gianmarco Bellucci, Rachele Bigi, Virginia Rinaldi, Daniela F. Angelini, Gisella Guerrera, Francesca C. Pignalosa, Sara Ilari, Marco Patrone, Sundararajan Srinivasan, Gabriel Cerono, Silvia Romano, Maria C. Buscarinu, Serena Martire, Simona Malucchi, Doriana Landi, Lorena Lorefice, Raffaella Pizzolato Umeton, Eleni AnastasiadouPankaj Trivedi, Arianna Fornasiero, Michela Ferraldeschi, IMSGC WTCCC2, Alessia Di Sapio, Gerolama Marfia, Eleonora Cocco, Diego Centonze, Antonio Uccelli, Dario Di Silvestre, Pierluigi Mauri, Paola de Candia, Sandra D’Alfonso, Luca Battistini, Cinthia Farina, Roberta Magliozzi, Richard Reynolds, Sergio E. Baranzini, Giuseppe Matarese, Marco Salvetti (Lead / Corresponding author), Giovanni Ristori

Postgraduate Medicine

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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.

Original language	English
Article number	e2418783122
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	122
Issue number	14
Early online date	4 Apr 2025
DOIs	https://doi.org/10.1073/pnas.2418783122
Publication status	Published - 8 Apr 2025

Keywords

autoimmunity
Epstein–Barr virus
multiple sclerosis

ASJC Scopus subject areas

General

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10.1073/pnas.2418783122Licence: CC BY-NC-ND

Final published versionFinal published version, 1.01 MBLicence: CC BY-NC-ND

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Mechelli, R., Umeton, R., Bellucci, G., Bigi, R., Rinaldi, V., Angelini, D. F., Guerrera, G., Pignalosa, F. C., Ilari, S., Patrone, M., Srinivasan, S., Cerono, G., Romano, S., Buscarinu, M. C., Martire, S., Malucchi, S., Landi, D., Lorefice, L., Umeton, R. P., ... Ristori, G. (2025). A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 122(14), Article e2418783122. https://doi.org/10.1073/pnas.2418783122

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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.",

keywords = "autoimmunity, Epstein–Barr virus, multiple sclerosis",

author = "Rosella Mechelli and Renato Umeton and Gianmarco Bellucci and Rachele Bigi and Virginia Rinaldi and Angelini, {Daniela F.} and Gisella Guerrera and Pignalosa, {Francesca C.} and Sara Ilari and Marco Patrone and Sundararajan Srinivasan and Gabriel Cerono and Silvia Romano and Buscarinu, {Maria C.} and Serena Martire and Simona Malucchi and Doriana Landi and Lorena Lorefice and Umeton, {Raffaella Pizzolato} and Eleni Anastasiadou and Pankaj Trivedi and Arianna Fornasiero and Michela Ferraldeschi and {IMSGC WTCCC2} and Sapio, {Alessia Di} and Gerolama Marfia and Eleonora Cocco and Diego Centonze and Antonio Uccelli and Silvestre, {Dario Di} and Pierluigi Mauri and {de Candia}, Paola and Sandra D{\textquoteright}Alfonso and Luca Battistini and Cinthia Farina and Roberta Magliozzi and Richard Reynolds and Baranzini, {Sergio E.} and Giuseppe Matarese and Marco Salvetti and Giovanni Ristori",

note = "Publisher Copyright: {\textcopyright} 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).",

year = "2025",

month = apr,

day = "8",

doi = "10.1073/pnas.2418783122",

language = "English",

volume = "122",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Mechelli, R, Umeton, R, Bellucci, G, Bigi, R, Rinaldi, V, Angelini, DF, Guerrera, G, Pignalosa, FC, Ilari, S, Patrone, M, Srinivasan, S, Cerono, G, Romano, S, Buscarinu, MC, Martire, S, Malucchi, S, Landi, D, Lorefice, L, Umeton, RP, Anastasiadou, E, Trivedi, P, Fornasiero, A, Ferraldeschi, M, IMSGC WTCCC2, Sapio, AD, Marfia, G, Cocco, E, Centonze, D, Uccelli, A, Silvestre, DD, Mauri, P, de Candia, P, D’Alfonso, S, Battistini, L, Farina, C, Magliozzi, R, Reynolds, R, Baranzini, SE, Matarese, G, Salvetti, M & Ristori, G 2025, 'A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 122, no. 14, e2418783122. https://doi.org/10.1073/pnas.2418783122

A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis. / Mechelli, Rosella (Lead / Corresponding author); Umeton, Renato; Bellucci, Gianmarco et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 122, No. 14, e2418783122, 08.04.2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis

AU - Mechelli, Rosella

AU - Umeton, Renato

AU - Bellucci, Gianmarco

AU - Bigi, Rachele

AU - Rinaldi, Virginia

AU - Angelini, Daniela F.

AU - Guerrera, Gisella

AU - Pignalosa, Francesca C.

AU - Ilari, Sara

AU - Patrone, Marco

AU - Srinivasan, Sundararajan

AU - Cerono, Gabriel

AU - Romano, Silvia

AU - Buscarinu, Maria C.

AU - Martire, Serena

AU - Malucchi, Simona

AU - Landi, Doriana

AU - Lorefice, Lorena

AU - Umeton, Raffaella Pizzolato

AU - Anastasiadou, Eleni

AU - Trivedi, Pankaj

AU - Fornasiero, Arianna

AU - Ferraldeschi, Michela

AU - IMSGC WTCCC2

AU - Sapio, Alessia Di

AU - Marfia, Gerolama

AU - Cocco, Eleonora

AU - Centonze, Diego

AU - Uccelli, Antonio

AU - Silvestre, Dario Di

AU - Mauri, Pierluigi

AU - de Candia, Paola

AU - D’Alfonso, Sandra

AU - Battistini, Luca

AU - Farina, Cinthia

AU - Magliozzi, Roberta

AU - Reynolds, Richard

AU - Baranzini, Sergio E.

AU - Matarese, Giuseppe

AU - Salvetti, Marco

AU - Ristori, Giovanni

PY - 2025/4/8

Y1 - 2025/4/8

N2 - 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.

AB - 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.

KW - autoimmunity

KW - Epstein–Barr virus

KW - multiple sclerosis

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U2 - 10.1073/pnas.2418783122

DO - 10.1073/pnas.2418783122

M3 - Article

C2 - 40184175

AN - SCOPUS:105002420793

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 14

M1 - e2418783122

ER -

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

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