Theiler's virus-induced central nervous system disease in mice.

Theiler's viruses, which are common enteric pathogenes of mice, produce an unusual buphasic disease in the natural host following IC inoculation. There is an early phase of virus growth in CNS gray matter resulting in motor neuron degeneration and microglial proliferation. Since the spinal cord is the principal site of involvement, infected animals develop flaccid limb paralysis (early disease). Immunosuppression of the host during the early phase of infection augments virus growth and pathological lesions in gray matter, suggesting that TV causes a cytocidal infection of neurons. More importantly, surviving mice have persistent infection and pathological change limited to the spinal cord. There is marked mononuclear cell infiltration in the leptomeninges and white matter and concomitant primary demyelination. These changes are associated with a distinctive late-developing neurological disorder characterized by general inactivity, slowed movement, poor righting ability, and stimulus-sensitive extensor spasms. It appears that there are differences in host susceptibility to the development of late disease with the SJL/J inbred strain of mouse regularly showing the most severe clinical manifestations. Both humoral and cell-mediated immunity to TV antigen are delayed, reaching a maximum after 2 months; hence, this temporal sequence of the immune response is atypical of acute virus infections. Certain features of the late disease process favor an immune-mediated mechanism for demyelination, and this possibility is currently under investigation. The cells chronically supporting virus replication and the mechanisms of persistent infection remain to be elucidated.