A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (153)
Rosella Mechelli
Department for the Promotion of Human Sciences and Quality of Life, San Raffaele Roma University
Renato Umeton
Weill Cornell Medicine
Gianmarco Bellucci
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Rachele Bigi
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Virginia Rinaldi
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Daniela F. Angelini
Neuroimmunology Unit, Istituto Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia
Gisella Guerrera
Neuroimmunology Unit, Istituto Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia
Francesca C. Pignalosa
Department for the Promotion of Human Sciences and Quality of Life, San Raffaele Roma University
Sara Ilari
Istituto Ricovero e Cura a Carattere Scientifico San Raffaele
Marco Patrone
Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute
Sundararajan Srinivasan
Institute of Experimental Neurology & Division of Neuroscience, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute
Gabriel Cerono
Department of Neurology, University of California San Francisco Weill Institute for Neurosciences, University of California San Francisco
Silvia Romano
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Maria C. Buscarinu
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Serena Martire
Clinical Neurobiology Unit, Neuroscience Institute Cavalieri Ottolenghi
Simona Malucchi
Department of Neurology and Centri di Riferimento Regionale Sclerosi Multipla, University Hospital San Luigi Gonzaga
Doriana Landi
Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University
Lorena Lorefice
Multiple Sclerosis Center, Binaghi Hospital, Azienda Sanitaria Locale Cagliari, Department of Medical Sciences and Public Health, University of Cagliari
Raffaella Pizzolato Umeton
Department of Neurology, University of Massachusetts Medical School
Eleni Anastasiadou
Department of Clinical and Molecular Medicine, Sapienza University
Pankaj Trivedi
Department of Experimental Medicine, Sapienza University
Arianna Fornasiero
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Michela Ferraldeschi
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Alessia Di Sapio
Clinical Neurobiology Unit, Neuroscience Institute Cavalieri Ottolenghi
Gerolama Marfia
Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University
Eleonora Cocco
Multiple Sclerosis Center, Binaghi Hospital, Azienda Sanitaria Locale Cagliari, Department of Medical Sciences and Public Health, University of Cagliari
Diego Centonze
Antonio Uccelli
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Centre of Excellence for Biomedical Research, University of Genova
Dario Di Silvestre
Clinical Proteomics Laboratory, Institute for Biomedical Technologies
Pierluigi Mauri
Elixir Proteomics Laboratory, Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche
Paola de Candia
Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli “Federico II”
Luca Battistini
Neuroimmunology Unit, Istituto Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia
Cinthia Farina
Institute of Experimental Neurology & Division of Neuroscience, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute
Roberta Magliozzi
Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona
Richard Reynolds
Department of Brain Sciences, Faculty of Medicine, Imperial College London
Giuseppe Matarese
Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli “Federico II”
Marco Salvetti
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Giovanni Ristori
Centre for Experimental Neurological Therapies, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University
Lars Alfredsson
Helle Bach Søndergaard
Sergio E. Baranzini
Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco
Lisa F. Barcellos
Luisa Bernardinelli
David Booth
School of Life Sciences, University of Technology
Manuel Comabella
Alastair Compston
Chris Cotsapas
Department of Neurology, Yale School of Medicine
Sandra D’Alfonso
Department of Health Sciences, University of Eastern Piedmont, Interdisciplinary Research Center of Autoimmune Diseases
Efthimios Dardiotis
Philip L De Jager
Bénédicte Dubois
Federica Esposito
Betrand Fontaine
An Goris
Pierre-Antoine Gourraud
Giorgos Hadjigeorgiou
David A. Hafler
Jonathan L. Haines
Hanne F. Harbo
Stephen L. Hauser
Bernhard Hemmer
Roland Henry
Hillert
Rogier Hintzen
Noriko Isobe
Adrian J. Ivinson
Seema Kalra
Michael Khalil
Ingrid Kockum
Department of Clinical Neuroscience, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Centre for Molecular Medicine, Karolinska Institutet
Jeanette Lechner-Scott
Roland Martin
Filippo Martinelli-Boneschi
Jacob L. McCauley
Jorge R. Oksenberg
Tomas Olsson
Annette Oturai
Grant P. Parnell
Nikolaos A. Patsopoulos
Margaret A. Pericak-Vance
Neil Robertson
Janna Saarela
Stephen J. Sawcer
Joost Smolders
Graeme J. Stewart
Bruce Taylor
V. Wee Yong
Frauke Zipp
Ines Barroso
Jenefer M. Blackwell
Elvira Bramon
Matthew A. Brown
Juan P. Casas
Mark Caulfield
David Clayton
Aiden Corvin
Nick Craddock
Panos Deloukas
Peter Donnelly
Audrey Duncanson
Martin Farrall
Alistair Hall
Andrew Hattersley
Janusz Jankowski
Hugh S. Markus
Christopher G. Mathew
Mark McCarthy
Colin N.A. Palmer
Miles Parkes
Robert Plomin
Anna Rautanen
Nilesh Samani
Stephen Sawcer
John Todd
Richard C. Trembath
Ananth C. Viswanathan
Nicholas W. Wood
Jane Worthington
Chris C.A. Spencer
Gavin Band
Céline Bellenguez
Colin Freeman
Garrett Hellenthal
Eleni Giannoulatou
Matti Pirinen
Richard Pearson
Amy Strange
Zhan Su
Damjan Vukcevic
Cordelia Langford
Sarah E. Hunt
Sarah Edkins
Rhian Gwilliam
Hannah Blackburn
Suzannah J. Bumpstead
Serge Dronov
Matthew Gillman
Emma Gray
Naomi Hammond
Alagurevathi Jayakumar
Owen T. McCann
Jennifer Liddle
Simon C. Potter
Rathi Ravindrarajah
Michelle Ricketts
Matthew J. Waller
Paul Weston
Sara Widaa
Pamela Whittaker
Alexander Dilthey
Stephen Leslie
Loukas Moutsianas
Marc L. Perez
Gil McVean