Basis of neurovirulence in Sindbis virus encephalomyelitis of mice

Neuroadapted Sindbis virus (NSV) was selected by serial passage of wild-type Sindbis virus (SV) in mouse brain. After intracerebral inoculation of weanling mice, NSV causes a severe encephalomyelitis with hindlimb paralysis and high mortality; SV causes nonfatal mild disease. In order to determine the biologic basis of neurovirulence in vivo, these viral infections have been compared by using infectivity assays, light and electron microscopy, in situ hybridization, immunohistochemistry, and double-labeling for neural cell markers and viral RNA. More infectious virus is present in the central nervous system during NSV than during SV infection. After intracerebral inoculation, both viruses enter the central nervous system via the ependyma and spread to gray matter areas, including the ventral horns of the spinal cord. Their cellular targets are not different, and neuronal infection is prominent. NSV infects more neurons, and causes more severe injury than SV. In NSV infection, there is marked swelling of lumbar and thoracic neurons and their processes in the ventral horns. Relatively mild changes are detected in SV infection only by electron microscopy. Neuroadaptation likely occurs by increasing the efficiency of viral replication in neurons, rather than by a fundamental change in the cellular tropism or the topography of the infection in the central nervous system.