Innate immune determinants of viral induced paralysis: The role of glial cells in the pathogenesis of Neuroadapted Sindbis virus

Neuroadapted Sindbis virus (NSV) is a neuronotropic virus capable of inducing death of spinal motor neurons in mice and rats. Because Sindbis virus primarily infects neurons, and not glial cells, it is a unique system in which to study the innate response of these cells to perturbations within the central nervous system (CNS). Evidence of early, endogenous inflammatory factors as well as excitotoxicity strongly implicates the resident microglia and astrocytes as players in NSV pathogenesis. The overall hypothesis of this thesis is that astrocglia and microglia contribute to motor neuron loss in the spinal cords of NSV-infected mice by the activation of both inflammatory and excitotoxic processes in the CNS.; Astrocytes protect neurons by modulation of extracellular levels of the excitatory neurotransmitter, glutamate, via the expression of glutamate transporters. Excess glutamate at the neuronal synapse can be toxic to post-synaptic neurons and cause them to die a necrotic death (excitotoxicity). Studies presented here demonstrate that the primary astrocytic glutamate transporter, GLT-1, is downregulated in NSV-infected mice, indicative of a role for astrocytes in NSV pathogenesis. Furthermore, we have found that the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) represses the expression of GLT-1 on astrocytes. The source of endogenous TNF-alpha was not determined, though microglia and astroglial are both capable of expressing the cytokine.; Microglial activation in the NSV model appears to be a double-edged sword. Infection of C57BL/6 mice leads to a robust activation of microglia which likely contributes to the production of inflammatory cytokines and chemokines that can damage neurons. NSV infection of a mouse that is conditionally depleted of activated microglial cells are not protected, rather the pathogenesis is exacerbated in these animals indicating that microglial activation in the NSV model must confer some benefit. Additionally, Toll-like Receptor-3 (TLR-3) was investigated as a putative trigger of microglial activation, though TLR-3-deficient animals were not protected from NSV-mediated pathogenesis. Microglial cells are likely activated against NSV by alternative mechanisms not examined here.