Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis?

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS). The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers. These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS. This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS.

Keywords: EBV; immune response; miRNA; multiple sclerosis; post-transcriptional regulation.

Figure 1

Proposed interaction between EBV encoded miRNAs and cellular miRNAs in MS. In the circulation of MS patients, the level of different cellular miRNAs is dysregulated-either significantly upregulated (↑) or downregulated (↓) including miR-20a, miR-20b, miR-211, miR-93, miR-30a, and miR-146a. Disrupted homeostasis of miRNAs impacts the levels of target mRNAs of genes involved in the local immune response. Consequently, a response that is skewed toward the inflammatory phenotype dominates (for instance increased level of IL17a, IFNγ, and TNFα mRNAs and their gene products). Moreover, the increased level of MS exosomal let-7i results in the suppression of regulatory T cells, which otherwise counteract the action of inflammatory subsets of T cell. Circulating B cells (non-infected) and other cellular sources of miR-155 contribute to the elevated levels of miR-155, which is associated with increased titres of anti-EBNA1 antibodies in the circulation. It is interesting to know whether these two biomarkers act directly in a positive feedback loop. Additionally, increased levels of miR-155 directly or indirectly boosts the levels of EBV encoded miR-BART2 and miR-BHRF1 clusters, both of which support the survival of EBV infected B cells. While dysregulated cellular miRNAs feed the ongoing inflammation in MS, EBV encoded miRNAs protect surviving EBV infected cells from host antiviral immune response. One mechanism of evading immune response is by impairing the capacity of antigen presenting cells. EBV encoded miR-BHRF1-3 and miR-BART17 target TAP2 mRNA resulting in downregulation of TAP2 protein. This will diminish the event of processing and presenting EBV viral antigens on class I⁺ cells to EBV-specific CD8⁺T cells. In MS, anti-EBV CD8⁺T cells are chronically activated and functionally exhausted expressing the inhibitory molecules PD1 and TIM3. Within the same context, EBV encoded miR-BART2-5p target MICB mRNA leading to the compromised functionality of anti-EBV NK cells. The few surviving EBV infected cells may potentially influence the inflammatory population in the circulation and/or cross disrupted CNS barriers. The level of cellular miR-31 rises in dendritic cells increasing the potential of infiltrating the brain and spinal cord by different immune cells including the few EBV infected cells. In MS circulation, the expression of erythrocytes miR-30b-5p, miR-3200-3p and miR-3200-5p is increased, making them a useful biomarker for monitoring disease activity. All together, these events contribute to MS pathology hallmarks such as reactive gliosis elicited by activated microglia and astrocytes (right panel).