Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9

• Published in: PloS one 2018-07, Vol.13 (7), p.e0200546-e0200546
• Main Authors: Salloum, Noor, Hussein, Hadi M, Jammaz, Rana, Jiche, Sara, Uthman, Imad W, Abdelnoor, Alexander M, Rahal, Elias A
• Format: Article
• Language: English
• Subjects: Animals; Arthritis; Autoimmune diseases; Biology and life sciences; Care and treatment; Correlation; CTLA-4 protein; Cytokines; Deoxyribonucleic acid; Development and progression; DNA; DNA, Viral - immunology; Epstein-Barr virus; Female; Gene expression; Genetic aspects; Health aspects; Helper cells; Herpes viruses; Herpesvirus 4, Human - immunology; Immunoglobulins; Immunology; Infections; Inhibitors; Interleukin; Interleukin-17; Interleukin-17 - immunology; Interleukins; Leukocytes (mononuclear); Linearity; Lupus; Lymphocytes; Lymphocytes T; Lymphoma; Lymphomas; Medicine and health sciences; Mice; Mice, Inbred BALB C; Oligonucleotides; Pathology; Peripheral blood mononuclear cells; Physiological aspects; Rheumatoid arthritis; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Therapeutic targets; TLR9; TLR9 protein; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - immunology; Toll-like receptors; Transplants & implants; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0200546

Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes.