Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients

Abstract

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified EBV-encoded BART9-3p and BART15 miRNAs in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of BART9-3p (18.4-fold) and BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of miR-21-5p and miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group in comparison to those obtained from the HC group. The levels of Interferon gamma (IFN-{gamma}), interleukin-1{beta} (IL-1{beta}), interleukin- 6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF- {beta}), and tumor necrosis factor alpha (TNF-) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-{beta} (8.5- fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-{beta}:TNF- and TGF-{beta}:IFN-{gamma} attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. Remarkable stimulation of EBV BART9-3p, BART15 miRNAs, and inflammatory cytokines expression in CSF exosomes confers a substantial link between EBV in MS onset and also the infection-to-MS transition.