The response of intrinsic brain cells to virus infection in the central nervous system (CNS) can influence virus infection in the brain and the clinical outcome of disease. Our studies have focused on two animal models of virus-mediated neuropathogenesis to determine the host response proteins that regulate disease induction. We have identified several host response proteins that are upregulated in the CNS following neurovirulent retrovirus infection or bunyavirus infection and may influence neuronal damage. In 2013, we primarily focused on examining the role of the innate immune response in mediating neuronal death during virus infection. Our previous studies with primary neuronal cultures indicating that stimulation of neurons through pattern recognition receptors (PRRs) resulted in neuronal death. We examined a similar pathway during virus infection and identified a molecule SARM1 (sterile alpha and TIR-containing motif 1) as a mediator of LACV-mediated neuronal death. Neurons deficient in SARM1 had reduced virus-induced cell death despite similar virus levels. Similar results were observed in vivo with SARM1-/- mice. Examination of the mechanism of SARM1-mediated cell death demonstrated SARM1 localization to the mitochondria, induction of oxidative stress response and mitochondrial damage. Induction of SARM1 during LACV infection was dependent of the RIG-I/MAVS pathway, but was independent of the type I IFN response. These studies indicate that activation of anti-viral signaling mechanisms in neurons can lead to neuronal damage through the upregulation of SARM1. Targeting SARM1-mediated cell death may be useful in limiting neuronal damage during virus infections.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$432,124
Indirect Cost
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State
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