Innate immune response contributes to virus-mediated neuronal death through activation of SARM (170.2)

Abstract

Abstract Neuronal cell death is a hallmark of various neurological diseases including virus infection. The innate immune response in the CNS contributes to neuronal damage through cytokine and neurotoxin production as well as the recruitment of inflammatory cells. However, the role of the innate immune response in the induction of neuronal death is poorly understood. La Crosse virus (LACV), which is a major cause of pediatric encephalitis in the United States, predominantly infects neurons and is associated with neurodegenerative changes. Infection results in neuronal apoptosis. In the current studies we identified sterile alpha and HEAT/Armadillo motif containing 1 (SARM1) protein, a negative regulator of TLR signaling, as a moderator of LACV induced neuronal apoptosis. SARM 1 was induced in neurons following LACV infection and SARM1 knock down studies in neurons demonstrated increased viability during LACV infection as compared to wild-type controls. Direct TLR stimulation of neurons induced SARM 1 which correlated with neuronal apoptosis. Thus, SARM induced as a response to innate immune activation appears to contribute to neuronal death. We are currently investigating the mechanisms underlying SARM induced neuronal death following LACV infection.