Alphaviruses infect neurons in the brain and spinal cord of a variety of mammals and cause acute encephalomyelitis. These infections vary from asymptomatic diseases to ones producing severe paralysis and death. Outcome from infection is determined by the number of neurons which become infected and whether these cells survive the infection. The number of neurons which become infected can be influenced by both the adaptive and innate immune responses to the virus. Antiviral antibody and type I interferons inhibit virus replication and spread, thereby limiting the number of infected cells. The cellular immune response to non-structural proteins (NSP) of the virus protects the host by a different mechanism which may involve promoting the survival and functional recovery of infected neurons. Experiments proposed here are designed, first, to test the hypothesis that immunization of mice with a recombinant vaccinia virus expressing NSP of Sindbis virus (SV) protects against an otherwise lethal challenge with a neuro-virulent strain of SV in a manner whereby infected neurons survive and recover function rather than die and, then, to understand the mechanism(s) underlying these events. Specifically, I propose (1) to quantify the amounts of virus-induced neuronal death in protected and control mice using immunohistochemical techniques, (2) to identify the specific components of the cellular immune response involved in protection using both adoptive transfer experiments and various immune deficient strains of mice, and (3) to detected cellular genes induced in the nervous system that are associated with protection using various molecular techniques. Studying the mechanisms of neuronal survival and death in this setting may have implications for understanding other neurodegenerative diseases.
