Viruses and Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.

Activation of Necroptosis in Multiple Sclerosis

“…This finding may have significance in the etiology of MS: since several members of the herpesvirus family, which have been implicated in the etiology of MS (Virtanen and Jacobson, 2012), express v-FLIPs, the viral homologues of cellular FLIPs, and can inhibit caspase-8 activation. Our data also suggest the possibility that inhibition of caspase-8 by v-FLIPs might be involved in promoting the onset of MS…”

Endoplasmic reticulum stress and inflammation in the central nervous system

“…This phenomenon, molecular mimicry, is considered a potential mechanism by which pathogens break self-immunological tolerance and induce an autoimmune reaction. Pathogens sharing high degrees of peptide similarity with myelin-derived peptides include Human Herpes virus type 6 and Epstein Barr virus [182]. The inflammatory milieu brought about by infiltrating innate immune cells and reactive T lymphocytes in the initial stages of the disease promotes further T cell polarization to the T H 1 or T H 17 subsets to amplify neuronal damage.…”

Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

“…Although specific infectious agents have not been linked to MS, epidemiological studies suggest that herpes simplex virus type-1 (HSV-1), human herpes virus type-6 (HHV-6), T cell leukemia virus type-1, Epstein-Barr virus, influenza virus, and human picornaviruses, such as rhinovirus, may be associated with MS [reviewed in (Libbey and Fujinami, 2010) (Kriesel et al, 2004)], suggesting that environmental factors such as viral infections may be related to the development and/or exacerbation of MS in genetically susceptible individuals. In fact, viral antigens and virus-specific antibodies were detected in subsets of MS patients [reviewed in (Virtanen and Jacobson, 2012)]. Actually, antigens from HHV-6 were found in the MS plaques (Cermelli et al, 2003; Challoner et al, 1995; Soldan et al, 1997; Virtanen et al, 2011).…”