A specific viral cause of multiple sclerosis: One virus, one disease

Abstract

"Multiple sclerosis is an autoimmune disease," is heard so often that it is widely accepted as fact by the current generation of students and physicians. Yet, although it is undisputed that multiple sclerosis (MS) is immune mediated, an autoimmune mechanism remains unproven. Immune-mediated tissue damage can also result from viral infections in which the host immune response is directed to viral rather than self proteins, or as a consequence of nonspecific or bystander immune responses that change the local cytokine environment. Increasing evidence suggests that poorly controlled host immune responses account for much of the tissue damage in chronic infections, and it has been postulated that a similar mechanism may underlie many chronic diseases with features suggestive of an infectious causative factor, including MS. A recent study suggesting that oligodendrocyte death accompanied by microglial activation is the primary event in new MS lesion formation, rather than lymphocyte infiltration, could change the current mindset almost exclusively focused on autoimmunity. This review presents the rationale for considering MS a single disease caused by one virus, as well as the anticipated pattern of a persistent central nervous system infection, the application of Koch's postulates to viral discovery in MS as the causative agent, and tissue culture-independent genotypic approaches to viral discovery in MS.

Evidence linking HHV-6 with multiple sclerosis: an update

“…Interestingly, viruses have dominated the list of suspected agents; there have been few bacteria or parasites by comparison [5]. However, despite the subsequent isolation of the specific viruses responsible for the demyelinating diseases subacute sclerosing panencephalitis (SSPE: measles virus) and progressive multifocal leukoencephalopathy (PML: JC virus), the focus of the MS field has largely transitioned away from a single, unidentified agent (though some hold this view [6]) towards ubiquitous agents, particularly herpesviruses [5]. While there are numerous reports for other herpesviruses in MS, notably the sero-epidemiological data for human herpesvirus 4 (Epstein-Barr virus (EBV)) reviewed in [7, 8], this current review will focus solely on HHV-6.…”

Cardioviruses Are Genetically Diverse and Cause Common Enteric Infections in South Asian Children

“…One component of testing linkage between a new viral species and human disease is an appreciation of the full range of genetic diversity of the viral species since it is well established that distinct viral genotypes or even minor genetic variations can result in large changes in viral pathogenicity. Specific variants belonging to the two currently recognized species of the Cardiovirus genus, Theilovirus and Encephalomyocarditis virus (EMCV), have been shown to induce other demyelinating diseases (an animal model of multiple sclerosis), encephalitis, myocarditis, or type 1 diabetes in rodents (4,10,33,50,55). Cardioviruses typically replicate asymptomatically in the gastrointestinal tract following fecal-oral transmission, and some strains can replicate in the central nervous system following intracerebral injection, resulting in neurological symptoms.…”

The L-Coding Region of the DA Strain of Theiler's Murine Encephalomyelitis Virus Causes Dysfunction and Death of Myelin-Synthesizing Cells

“…The relative contribution in TMEV-IDD of a direct virus-mediated oligodendrocyte dysfunction/lysis vis-à-vis immune-mediated demyelination remains unclear, as is the case with other demyelinating diseases (19,43), including MS (2,10,18). In order to clarify the functions of selected DA virus genes, we made use of the Cre/loxP system to provide inducible and cell-type-specific expression of DA L in oligodendrocytes (and Schwann cells), a cell type in which DA virus is known to persist.…”

“…These results suggest that the expression of L plays a major role in the pathogenesis of TMEV-IDD. A virus infection and gene directly causing the death or dysfunction of oligodendrocytes may also underlie other virus-induced demyelinating diseases in which an immune-mediated mechanism has been stressed (19,43), as well as immune-mediated diseases in which virus involvement is not certain, such as MS (2,10,18).…”