Multiple Sclerosis and Viruses: « Liaisons Dangereuses »

Multiple sclerosis (MS) is a complex, multifactorial neurodegenerative disease with an aetiology that is still partially elusive. Several risk factors are associated with MS development including genetic predisposition and various environmental stressors; however, recently, viral infections have gained significant attention as a crucial environmental trigger. Despite the well-established link between Epstein-Barr virus (EBV) and MS susceptibility, a single-pathogen model fails to clearly characterise the molecular cascades driving the disease, suggesting that the transition from infection to autoimmune response involves more than one viral agent. In this review we examine the speculation that the interactions among different neurotropic viruses could serve a collective causative role in MS, which is under-researched in the literature at present. We summarise contradictory evidence on the role of different viral agents, including the Herpesviridae family (Human Cytomegalovirus, EBV, Herpes Simplex Viruses HSV-1 and HSV-2, and Varicella Zoster Virus), Paramyxoviridae family (Measles Virus and Rubella Virus), Influenza virus, SARS-CoV-2, and Human Endogenous Retroviruses (HERVs). Through interplay within shared molecular pathways, immune modulation, and activation of latent infections, these viruses may collectively influence the inflammatory and demyelinating processes that characterise MS. This review evaluates the etiological role of viral interplay in MS through the cumulative and interactive effects of these pathogens. The available epidemiological, immunological, and experimental data converge on the concept that viral co-exposures act synergistically to shape MS susceptibility in genetically predisposed individuals. Characterising these viral interactions presents a new research direction for the identification of novel biomarkers and the development of preventative strategies through the targeted control of viral networks.