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

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Title: A disease-specific convergence of host and Epstein-Barr virus genetics in multiple sclerosis.
Authors: Mechelli, Rosella1,2 rosella.mechelli@uniroma5.it, Umeton, Renato3,4,5, Bellucci, Gianmarco6, Bigi, Rachele6, Rinaldi, Virginia6, Angelini, Daniela F.7, Guerrera, Gisella7, Pignalosa, Francesca C.1,2, Ilari, Sara2, Patrone, Marco8, Srinivasan, Sundararajan9, Cerono, Gabriel10, Romano, Silvia6, Buscarinu, Maria C.6, Martire, Serena11,12,13, Malucchi, Simona14, Landi, Doriana15, Lorefice, Lorena16, Pizzolato Umeton, Raffaella17,18,19, Anastasiadou, Eleni20
Source: Proceedings of the National Academy of Sciences of the United States of America. 4/8/2025, Vol. 122 Issue 14, p1-11. 45p.
Subjects: RNA polymerase II, Viral genetics, Genetic variation, Gene expression, Viral variation
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. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: A disease-specific convergence of host and Epstein-Barr virus genetics in multiple sclerosis.
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  Data: <searchLink fieldCode="AR" term="%22Mechelli%2C+Rosella%22">Mechelli, Rosella</searchLink><relatesTo>1,2</relatesTo><i> rosella.mechelli@uniroma5.it</i><br /><searchLink fieldCode="AR" term="%22Umeton%2C+Renato%22">Umeton, Renato</searchLink><relatesTo>3,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Bellucci%2C+Gianmarco%22">Bellucci, Gianmarco</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Bigi%2C+Rachele%22">Bigi, Rachele</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Rinaldi%2C+Virginia%22">Rinaldi, Virginia</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Angelini%2C+Daniela+F%2E%22">Angelini, Daniela F.</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Guerrera%2C+Gisella%22">Guerrera, Gisella</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Pignalosa%2C+Francesca+C%2E%22">Pignalosa, Francesca C.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Ilari%2C+Sara%22">Ilari, Sara</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Patrone%2C+Marco%22">Patrone, Marco</searchLink><relatesTo>8</relatesTo><br /><searchLink fieldCode="AR" term="%22Srinivasan%2C+Sundararajan%22">Srinivasan, Sundararajan</searchLink><relatesTo>9</relatesTo><br /><searchLink fieldCode="AR" term="%22Cerono%2C+Gabriel%22">Cerono, Gabriel</searchLink><relatesTo>10</relatesTo><br /><searchLink fieldCode="AR" term="%22Romano%2C+Silvia%22">Romano, Silvia</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Buscarinu%2C+Maria+C%2E%22">Buscarinu, Maria C.</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Martire%2C+Serena%22">Martire, Serena</searchLink><relatesTo>11,12,13</relatesTo><br /><searchLink fieldCode="AR" term="%22Malucchi%2C+Simona%22">Malucchi, Simona</searchLink><relatesTo>14</relatesTo><br /><searchLink fieldCode="AR" term="%22Landi%2C+Doriana%22">Landi, Doriana</searchLink><relatesTo>15</relatesTo><br /><searchLink fieldCode="AR" term="%22Lorefice%2C+Lorena%22">Lorefice, Lorena</searchLink><relatesTo>16</relatesTo><br /><searchLink fieldCode="AR" term="%22Pizzolato+Umeton%2C+Raffaella%22">Pizzolato Umeton, Raffaella</searchLink><relatesTo>17,18,19</relatesTo><br /><searchLink fieldCode="AR" term="%22Anastasiadou%2C+Eleni%22">Anastasiadou, Eleni</searchLink><relatesTo>20</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 4/8/2025, Vol. 122 Issue 14, p1-11. 45p.
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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