Effect of Epstein-Barr Virus infection on gene regulation in immune cells of patients with Immune-Mediated Diseases

Abstract

It has been known that Epstein-Barr virus (EBV) can latently infect immune cells after the initial infection, and epidemiological studies have suggested its association with the onset of immune-mediated diseases (IMDs). However, the specific impact of EBV infection on IMDs pathology remains unclear. We quantified EBV load of B cell subsets (Naïve B cells, Unswitched memory B cells, Switched memory B cells, Double negative B cells, and Plasmablasts) in IMD patients as well as healthy control (HC) using bulk RNA sequencing data of 504 donors. The EBV load was clearly higher in IMD patients compared to HC. Furthermore, the wide range of EBV load in this dataset enabled us to assess the impact of EBV load on gene regulation. We found many examples of expression quantitative trait loci (eQTL) whose effects were associated with EBV load. Expression QTLs that exhibited larger effects with increasing EBV load were significantly overlapped with binding sites of transcription factors derived from the EBV genome. These EBV load-associated eQTLs exhibited high enrichment of systemic lupus erythematosus (SLE) GWAS signals, suggesting the mechanical link of EBV infection and the onset of the disease via gene regulation. These findings provide the first evidence of the influence of EBV infection on gene regulation in human primary cells and its association with the SLE onset and/or progression.