Viruses and neuroinflammation in multiple sclerosis

Abstract

In multiple sclerosis (MS), a relationship with viral infection has long been recognized, starting from clinical evidence of an association between infectious events and disease onset or relapse. Herpesviridae and human endogenous retroviruses (HERVs) are among the most studied viral families in MS. These exposures share the characteristic of being latent persisting infections with hidden or dormant phases that allow them to escape immune detection and reactivate upon exposure to several stimuli. Moreover, their preferential tropism for cells of the central nervous system (CNS) and immune system accounts for their plausible pathogenic role in neuroinflammation. Compartmentalized and persisting chronic inflammation within the CNS is a feature of MS, as compared with other forms of self-limiting demyelinating conditions. This has suggested the existence of a persistent agent (such as a latent virus) that sustains the pathogenic loop and determines consequent tissue damage, failure of reparative mechanisms, and accumulation of neurological deficits. This review aims to survey the literature on the relationship between viruses and MS, with special reference to the levels of complexity in the loop that can modify disease risk, namely non-genetic risk factors (including viral components) that interact with each other and with genetic variants, with possible effects on both the host and viral genome. We will also review the latest advances in therapeutic targeting virus-induced dysregulations in MS.

GWAS associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis

“…As a matter of fact, the sequence variability of these regions and the strict time-dependence of their transcription could be instrumental to adaptive features; however, these same features make these regions susceptible to become dysfunctional or to be the targets of pathogenic interaction. In some instances, these detrimental interactions come from outside the cell, such as in the case of EBV interference with host transcription (Mechelli R., 2021, Accepted; Park et al, 2020), and the pathogenic consequences of vitamin D deficiency; in other cases, the dysfunction develops within the cell, such as the tumorigenic activity of AID in B cells (Meng et al, 2014; Qian et al, 2014).…”

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

“…High titers of anti-HHV6 antibodies are epidemiologically associated to MS development risk, both alone and by interacting with anti-EBNA1 titers ( 126 ). Several HHV-6 pathogenetic mechanisms have been pinpointed in MS: enhancing on-site inflammation in MS lesion, mimicry toward myelin antigens, direct provocation of apoptosis of glial cells and consequent epitope spreading, and induction of neuronal death due to glutamate excitotoxicity ( 10 ).…”

“…Notably, HERVs are also associated to CFS (131). When expressed, HERV-W Env protein acts as a superantigen, activates CNS-oriented T lymphocytes and microglia, sustaining a proinflammatory state and impairing myelin homeostasis (10). These mechanisms translate to MS relapses and progression, to the point that MSRV proteins have been candidate as biomarkers and therapeutic targets in MS (132,133).…”

“…It is plausible that MS neurodegenerative and inflammatory processes start years before the epiphany of radiological and clinical manifestations (4)(5)(6)(7). In this context, viral agents are good candidates to uncover the disease, as they are capable to precipitate the dysimmune process via multiple mechanisms: molecular mimicry, bystander activation, epitope spreading, autoreactive immune cell survival and immortalization, regulome modifications (3,(8)(9)(10). Thus, the selection and global spread of a novel human-infecting virus represents an experimental challenge to study virus-associated diseases, including MS.…”

Recent Advances in Unveiling the Role of Beta-Herpesviruses in Autoimmune Diseases

“…Recently, the putative role of HCMV and HHV-6 infection has been investigated in autoimmune diseases, such as systemic sclerosis [12][13][14][15], multiple sclerosis [16,17], systemic lupus erythematosus [18], and Hashimoto's Thyroiditis [19].…”