Elucidating neuronal innate immune mechanisms in the central nervous system.

Abstract

Abstract Neurotropic viruses are the most common cause of infectious encephalitis. Published studies have increased our understanding of how resident glial cells and infiltrating leukocytes contribute to neuroimmune responses during pathogen invasion. However, neuron-specific immune responses remain poorly described. Neurons are readily infected by neurotropic viruses, but studies show neuronal stimulation by viral components poorly induces pathways that are critical for viral control, such as the type I interferon (IFN) response. This leads our central question of how do neurons orchestrate effective antiviral immunity during CNS infection? To probe type I IFN responses in the CNS, I have developed an intracranial neonatal infection model using La Crosse Virus (LACV), an emerging RNA virus. Preliminary data show that infections of C57Bl/6 wild-type, Type I IFN receptor (IFNAR) receptor knock-out (KO), and non-canonical type I IFN pathway (STING) KO neonates with both wild-type LACV and LACV-ΔNSs (lacks the known type I IFN antagonist, NSs) viruses causes severe disease and reduced survival of neonates. IFNAR KO and STING KO mice succumb to disease earlier than C57Bl/6 mice. Additionally, in all genetic backgrounds, viral titers have an inverse relationship with survival. Future work will assess cell-specific infectivity of LACV and type I IFN responses in the CNS. I have also developed an in vitro infection pipeline where primary neurons isolated and cultured from mice are infected and further characterized using fluorescence in situ hybridization and RNA-sequencing. I plan to infect neurons of differential maturation states with LACV-ΔNSs and evaluate changes in gene expression compared to uninfected, bystander cells. Supported by Penn Presidential Fellowship.