Theiler's virus infection: a model for multiple sclerosis

Abstract

Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans.

FIG. 1.

Comparison of the immune responses to TMEV of sensitive (SJL) and resistant (B6) strains of mice infected i.c. with the virus. Differences in the immune responses of these strains of mice to TMEV are summarized during early acute disease (polioencephalomyelitis). Resistant strains of mice completely clear the virus and do not develop demyelinating disease. In contrast, sensitive strains of mice fail to completely clear the virus and develop persistent viral infection associated with low virus titers and late chronic demyelinating disease, characterized by massive mononuclear cell inflammatory infiltrates and demyelinating lesions.

FIG. 2.

Kinetic study of the proportions of CD3⁺ TUNEL-positive cells and of CD3⁺ Bcl-2⁺ cells in the CNS of TMEV-infected SJL mice during early acute disease and late chronic demyelinating disease. During early acute disease, high proportions of CD3⁺ TUNEL-positive cells and minimal proportions of CD3⁺ Bcl-2⁺ cells were observed in the CNS of these mice. However, during late chronic demyelinating disease, the proportions of CD3⁺ TUNEL-positive cells were minimal and those of CD3⁺ Bcl-2⁺ cells were high in the CNS of TMEV-infected SJL mice. Data from reference .