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

神经元成熟对抗病毒 I 型干扰素途径活性的作用。

• 批准号: 8022902
• 负责人: Jocelyn R Farmer
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022902
• 关键词: Adult; Age; Antiviral Agents; Arbovirus Infections; Arboviruses; Brain; Cells; Child; Childhood; Clinical; Data; Defect; Development; Disease; Disease Outbreaks; Encephalitis; Goals; Human; ISGF3G protein; Immune; Immune response; In Vitro; Infection; Interferon Type I; Interferons; Knock-out; Laboratories; Lead; Molecular; Morbidity - disease rate; Mus; Neuraxis; Neurologic; Neurons; Pathway interactions; Patients; Peripheral; Population; Predisposition; Production; Public Health; Role; Severities; Severity of illness; Signal Pathway; Site; Testing; Up-Regulation; Viral; Viral Encephalitis; Viral Load result; Virus Diseases; Virus Replication; Western Equine Encephalitis Virus; Work; age related; farmer; gain of function; human embryonic stem cell; in vivo; innate immune function; mouse model; neuroblastoma cell; neurotropic; neurovirulence; novel; receptor; response

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.

描述（由申请人提供）：嗜神经虫媒病毒是世界范围内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，是一个主要的公共卫生问题。虫媒病毒性脑炎对儿童尤其具有破坏性，与成人相比，儿童更常发展为严重的脑病和永久性的神经系统后遗症。这种戏剧性的年龄相关的临床表现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成熟依赖性虫媒病毒易感性，其中神经系统疾病的严重程度与中枢神经系统（CNS）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，未成熟的感染中枢神经系统中病毒复制持续增加。这些数据支持了一种假设，即成熟依赖性的变化发生在CNS对虫媒病毒感染的先天免疫反应中，发生在病毒复制的部位，即CNS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抗病毒途径）在虫媒病毒在中枢神经系统内的限制中的重要性。我们的实验室进一步证明，抗病毒I型IFN通路活性在人类神经元中是成熟依赖的。我们使用分化的人类神经母细胞瘤细胞表明，未成熟的神经元对I型干扰素治疗不太敏感，这导致对西部马脑炎病毒（WEEV）的易感性增加。本提案的目标是扩展我们之前的结果，并研究人类神经祖细胞（npc）和成熟人类神经元中抗病毒I型IFN通路的活性。NPCs在未成熟的中枢神经系统中富集；并且在体内被虫媒病毒特异性靶向。然而，人类npc的先天抗虫病毒功能尚未被直接评估。我们假设，与成熟神经元相比，npc减少了I型IFN通路成分的表达，这导致对I型IFN的反应降低，对WEEV的易感性增加。这一假设将通过两个特定目的进行验证：1)检测I型IFN通路组分在人类npc与成熟人类神经元中的表达和功能。2)在WEEV感染的情况下，检测npc与成熟神经元的先天免疫功能。本研究将探讨人类npc天生的抗weev能力。最终，我们的结果可以提供一种新的机制来解释小儿中枢神经系统虫媒病毒感染的严重程度。