Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing Systemic Lupus Erythematosus

Ali Afrasiabi; Jeremy Thomas Keane; Lawrence T C Ong; Hamid Alinejad-Rokny; Nicole Louise Fewings; David Richmond Booth; Grant Peter Parnell; Sanjay Swaminathan

doi:10.1016/j.jaut.2021.102781

Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing Systemic Lupus Erythematosus

J Autoimmun. 2022 Feb:127:102781. doi: 10.1016/j.jaut.2021.102781. Epub 2021 Dec 21.

Authors

Ali Afrasiabi¹, Jeremy Thomas Keane², Lawrence T C Ong², Hamid Alinejad-Rokny³, Nicole Louise Fewings⁴, David Richmond Booth², Grant Peter Parnell⁵, Sanjay Swaminathan⁶

Affiliations

¹ EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia; BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.
² EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
³ BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia; Health Data Analytics Program Leader, AI-enabled Processes (AIP) Research Centre, Macquarie University, Sydney, 2109, Australia; Core Member of UNSW Data Science Hub, The University of New South Wales (UNSW Sydney), Sydney, NSW, 2052, Australia.
⁴ EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia; Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁵ EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia; Biomedical Informatics and Digital Health, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: grant.parnell@sydney.edu.au.
⁶ EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Medicine, Western Sydney University, Sydney, NSW, Australia. Electronic address: sanjay.swaminathan@sydney.edu.au.

PMID: 34952359
DOI: 10.1016/j.jaut.2021.102781

Abstract

To investigate the molecular mechanisms through which Epstein-Barr virus (EBV) may contribute to Systemic Lupus Erythematosus (SLE) pathogenesis, we interrogated SLE genetic risk loci for signatures of EBV infection. We first compared the gene expression profile of SLE risk genes across 459 different cell/tissue types. EBV-infected B cells (LCLs) had the strongest representation of highly expressed SLE risk genes. By determining an SLE risk allele effect on gene expression (expression quantitative trait loci, eQTL) in LCLs and 16 other immune cell types, we identified 79 SLE risk locus:gene pairs putatively interacting with EBV infection. A total of 10 SLE risk genes from this list (CD40, LYST, JAZF1, IRF5, BLK, IKZF2, IL12RB2, FAM167A, PTPRC and SLC15A) were targeted by the EBV transcription factor, EBNA2, differentially expressed between LCLs and B cells, and the majority were also associated with EBV DNA copy number, and expression level of EBV encoded genes. Our final gene network model based on these genes is suggestive of a nexus involving SLE risk loci and EBV latency III and B cell proliferation signalling pathways. Collectively, our findings provide further evidence to support the interaction between SLE risk loci and EBV infection that is in part mediated by EBNA2. This interplay may increase the tendency towards EBV lytic switching dependent on the presence of SLE risk alleles. These results support further investigation into targeting EBV as a therapeutic strategy for SLE.

Keywords: EBNA2; EBV; GWAS; Lytic; SLE; eQTL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes
Epstein-Barr Virus Infections* / complications
Epstein-Barr Virus Infections* / genetics
Herpesvirus 4, Human / genetics
Humans
Lupus Erythematosus, Systemic* / genetics
Lupus Erythematosus, Systemic* / metabolism
Transcriptome