The role of neuronal maturation on antiviral type I interferon pathway activity.

描述（由申请方提供）：嗜神经虫媒病毒是全球病毒性脑炎的主要病原体，由于其广泛传播的潜力和目前缺乏有效的抗病毒药物，因此是一个主要的公共卫生问题。虫媒病毒性脑炎在儿童中尤其具有破坏性，与成人相比，儿童更经常发展为严重的脑炎疾病和永久性神经系统后遗症。这种与年龄相关的临床表现的显著差异在细胞和分子水平上仍然知之甚少。 在小鼠模型中观察到对虫媒病毒的成熟依赖性易感性，其中神经系统疾病的严重程度与中枢神经系统（CNS）中的病毒滴度呈正相关。令人惊讶的是，在缺乏外周和适应性免疫防御的情况下，增加的病毒复制持续存在于未成熟的感染CNS中。这些数据支持的假设，成熟依赖性的变化发生在中枢神经系统的先天性免疫反应的虫媒病毒感染的病毒复制的网站，中枢神经系统神经元。 敲除研究已经阐明了I型IFN途径（一种经典的细胞先天性抗病毒途径）对CNS内虫媒病毒限制的重要性。我们的实验室已经进一步证明，抗病毒I型干扰素途径的活动是人类神经元的成熟依赖性。我们已经表明，使用分化的人神经母细胞瘤细胞，未成熟的神经元是不太敏感的I型干扰素治疗，这导致增加的易感性西方马脑炎病毒（WEEV）。 这个建议的目标是扩展我们以前的结果，并调查抗病毒I型干扰素通路的活性在人类神经祖细胞（NPC）和成熟的人类神经元。NPC在未成熟的CNS中富集;并且在体内被虫媒病毒特异性靶向。然而，人类NPC的先天抗虫媒病毒功能尚未直接评估。我们推测，与成熟神经元相比，NPC具有降低的I型IFN途径组分表达，这导致对I型IFN的反应降低和对WEEV的易感性增加。该假设将通过两个特定目的进行测试：1）检查I型IFN途径组分在人NPC中相对于成熟人神经元中的表达和功能。 2)在WEEV感染的背景下，检查NPC与成熟神经元的先天免疫功能。这项提案将调查人类NPC的先天抗WEEV能力。最终，我们的研究结果可以提供一个新的机制来解释虫媒病毒感染的严重性，在小儿中枢神经系统。

DESCRIPTION (provided by applicant): 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.