The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype.

Autor:	Keane JT; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia., Afrasiabi A; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia; BioMedical Machine Learning Lab, The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia., Schibeci SD; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia., Swaminathan S; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia; Department of Medicine, Western Sydney University, Sydney, NSW 2560, Australia., Parnell GP; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. Electronic address: grant.parnell@sydney.edu.au., Booth DR; Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. Electronic address: david.booth@sydney.edu.au.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2021 Sep; Vol. 71, pp. 103572. Date of Electronic Publication: 2021 Sep 03.
DOI:	10.1016/j.ebiom.2021.103572
Abstrakt:	Background: Epstein-Barr virus (EBV) infection may be necessary for the development of Multiple sclerosis (MS). Earlier we had identified six MS risk loci that are co-located with binding sites for the EBV transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) in EBV-infected B cells (lymphoblastoid cell lines - LCLs). Methods: We used an allele-specific chromatin immunoprecipitation PCR assay to assess EBNA2 allelic preference. We treated LCLs with a peptide inhibitor of EBNA2 (EBNA2-TAT), reasoning that inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2. Findings: We found that EBNA2 binding was dependent on the risk allele for five of these six MS risk loci (p < 0·05). Treatment with EBNA2-TAT significantly altered the expression of TRAF3 (p < 0·05), CD40 (p < 0·001), CLECL1 (p <0·0001), TNFAIP8 (p < 0·001) and TNFRSF1A (p < 0·001). Interpretation: These data suggest that EBNA2 can enhance or reduce expression of the gene depending on the risk allele, likely promoting EBV infection. This is consistent with the concept that these MS risk loci affect MS risk through altering the response to EBNA2. Together with the extensive data indicating a pathogenic role for EBV in MS, this study supports targeting EBV and EBNA2 to reduce their effect on MS pathogenesis. Funding: Funding was provided by grants from MS Research Australia, National Health and Medical Research Council of Australia, Australian Government Research Training Program, Multiple Sclerosis International Federation, Trish Multiple Sclerosis Research Foundation. Competing Interests: Declaration of Competing Interest Funding for materials for the current manuscript were provided by MS Research Australia Project and Incubator grants. Australian Government financial support was provided to JTK and AA through the Research Training Program, and to DRB by a National Health and Medical Research Council of Australia fellowship. GPP was supported by an MS Research Australia Postdoctoral Fellowship and a Trish Multiple Sclerosis Research Foundation Project Grant. The authors declare no competing financial and non-financial interests. (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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