Neurotropic arboviruses are the leading causative agents of iral encephalitis worldwide and are a major public health concern due to their potential for wide dissemination and the current lack of effective antiviral agents. Arboviral encephalitis is particularly devastating in children, who more frequently develop severe encephalitic disease and permanent neurologic sequelae in comparison to adults. This dramatic age- related difference in clinical presentation remains poorly understood at the cellular and molecular level. Maturation-dependent susceptibility to arbovirus is observed in the mouse model, where neurologic disease severity correlates positively with viral titer in the central nervous system (CNS). Surprisingly, in the absence of peripheral and adaptive immune defenses, increased viral replication persists in the immature infected CNS. These data support the hypothesis that maturation-dependent changes occur in the innate immune response of the CNS to arbovirus infection at the site of viral replication, the CNS neuron. Knockout studies have elucidated the importance of the type I IFN pathway, a classic cellular innate antiviral pathway, on arbovirus restriction within the CNS. Our laboratory has further demonstrated that antiviral type I IFN pathway activity is maturation-dependent in human neurons. We have shown using differentiated human neuroblastoma cells that immature neurons are less sensitive to type I IFN treatment, which results in increased susceptibility to western equine encephalitis virus (WEEV). The goal of this proposal is to extend our previous results and investigate antiviral type I IFN pathway activity in human neuroprogenitor cells (NPCs) and mature human neurons. NPCs are enriched in the immature CNS;and specifically targeted by arbovirus in vivo. However, the innate anti-arboviral function of human NPCs has yet to be directly assessed. We hypothesize that, in comparison to mature neurons, NPCs have decreased type I IFN pathway component expression, which results in decreased response to type I IFN and increased susceptibility to WEEV. This hypothesis will be tested through two specific aims: 1) Examine the expression and function of type I IFN pathway components in human NPCs versus mature human neurons. 2) Examine the innate immune function of NPCs versus mature neurons In the context of WEEV infection. This proposal will investigate the innate anti-WEEV competency of human NPCs. Ultimately our results could provide a novel mechanism to explain the severity of arbovirus infection in the pediatric CNS.
|Farmer, Jocelyn R; Altschaefl, Kate M; O'Shea, K Sue et al. (2013) Activation of the type I interferon pathway is enhanced in response to human neuronal differentiation. PLoS One 8:e58813|
|Peltier, Daniel C; Lazear, Helen M; Farmer, Jocelyn R et al. (2013) Neurotropic arboviruses induce interferon regulatory factor 3-mediated neuronal responses that are cytoprotective, interferon independent, and inhibited by Western equine encephalitis virus capsid. J Virol 87:1821-33|