MECHANISMS OF NEUROPATHOGENESIS IN BORNA DISEASE

博尔纳病的神经发病机制

• 批准号: 6185777
• 负责人: MADY HORNIG
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6185777
• 关键词: Macaca mulatta; RNA virus; apoptosis; behavior disorders; behavioral /social science research tag; cerebrospinal fluid; cytokine; disease /disorder model; humoral immunity; laboratory rat; magnetic resonance imaging; model design /development; nervous system infection; neuropathology; neurotropic virus; newborn animals; perinatal; positron emission tomography; postmortem; psychomotor function; virus diseases; virus infection mechanism

DESCRIPTION (Applicant's Abstract): Borna disease virus (BDV) is a newly classified RNA virus that infects the CNS of warm blooded animals to cause disturbances of movement and behavior. Natural infection has been confirmed only in horses, sheep, cattle, birds, and cats; however, primates can be infected experimentally. Although the data remain controversial, several investigators have reported evidence of infection in schizophrenia and affective disorders. Most previous work in BDV pathogenesis has focused on infected adult immunocompetent rodents and ungulates where dramatic disturbances in behavior, limbic circuitry, and monoamine neurotransmitter systems are reminiscent of aspects of some neuropsychiatric syndromes (autism, schizophrenia, or bipolar disorder). While these models are intriguing they are associated with CNS inflammation, marked loss of brain mass and gliosis and may be less relevant to neuropsychiatric diseases than those in neonatally infected rats where BDV induces subtle disturbances of behavior, and hippocampal and cerebellar dysgenesis without inflammatory cell infiltration. The broad objectives of this project will be to: (1) determine the mechanisms by which viral infections alter CNS architecture and function without invoking infiltrating inflammatory elements and (2) establish and investigate nonhuman primate models for BDV infection. Whereas models for persistent tolerant infection of neonatal rats have been described, nonhuman primate studies have been pursued only in acutely infected adult rhesus macaques. Studies proposed here will clarify whether primates can be infected in the perinatal period and, if so, whether the clinical, behavioral, and neuropathologic sequelae are consistent with human psychiatric disease. The investigators hypothesize that perinatal infections of Rhesus monkeys will manifest as subtle neurobehavioral and neuropathologic disturbances in a primate counterpart to the neonatal rat model of persistent BDV infection. They further propose that elucidation of the pathogenesis of such neurologic dysfunction through more extensive studies of neonatal BDV infection of rats will provide critical information about mechanisms of viral-CNS interactions that will then permit more focused, informed investigations in humans and nonhuman primates. Specific aims in the neonatal rat model are: i) characterize the nature of the behavioral, cognitive, and motor deficits; ii) examine the neuropathology associated with the neurologic abnormalities; iii) evaluate changes in levels of cytokines as potential mediators of BDV-related damage; iv) discern whether apoptosis contributes to the neuropathology observed after neonatal infections and v) assess regional changes in neurotransmitter and neuroendocrine systems following neonatal BDV infection. The specific aims of the primate component of this application are to: 1) establish nonhuman primate models for BDV CNS infection using fetal and weanling Rhesus macaques; 2) determine the timecourse of the humoral immune response to BDV in infected fetal (intraventricular infection in utero) and weanling (intracerebral or intranasal infection) Rhesus macaques; 3) assess whether BDV nuclei acids can be detected in peripheral white blood cells (WBC) of infected Rhesus macaques; in the event that WBC are found to contain BDV nucleic acids can be detected in peripheral white blood cells (WBC) or infected Rhesus macaques; and in the event that WBC are found to contain BDV nucleic acids, to determine the distribution of BDV nucleic acids with respect to cell type and timecourse after infection; 4) define the hematologic, chemical, and virologic profile of cerebrospinal fluid (CFS) in infected fetal and weanling Rhesus macaques; 5) characterize the nature of any neurobehavioral, socioemotional, or motor deficits, and 6) evaluate neuropathology through in vivo (MRI and PET brain imaging) and postmortem analyses.

描述（申请人的摘要）：伯尔纳病毒病毒（BDV）是新的 分类的RNA病毒感染温暖血液的中枢神经系统引起 运动和行为的干扰。 自然感染已得到证实 仅在马，绵羊，牛，鸟和猫中；但是，灵长类动物可以是 经过实验感染。 尽管数据仍然存在争议，但有几个 研究人员报告了精神分裂症感染的证据和 情感障碍。 BDV发病机理上的大多数工作都集中在 感染的成人免疫能力啮齿动物，并在戏剧性 行为，边缘电路和单胺神经递质的干扰 系统让人联想到某些神经精神综合症的方面 （自闭症，精神分裂症或躁郁症）。 虽然这些模型是 有趣的是它们与中枢神经系统发炎，明显的大脑丧失有关 质量和神经病，可能与神经精神疾病相比，可能与 在新生儿感染的大鼠中，BDV引起微妙的干扰 行为，以及没有炎症的海马和小脑失调 细胞浸润。 该项目的广泛目标将是：（1） 确定病毒感染改变CNS体系结构的机制 和功能而无需调用浸润炎症元件，（2） 建立和研究非人类灵长类动物模型，以进行BDV感染。 而新生大鼠的持续耐受感染的模型已经 描述的是，非人类的灵长类研究仅在敏锐的 感染的成年恒河猕猴。 这里提出的研究将阐明是否 灵长类动物可以在围产期感染，如果是的话，是否 临床，行为和神经病理后遗症与人类一致 精神病。 研究人员假设围产期 恒河猴的感染将表现为微妙的神经行为和 新生大鼠的灵长类动物对应的神经病理障碍 持续性BDV感染的模型。 他们进一步提出了 这种神经功能障碍通过更广泛的发病机理 大鼠新生儿BDV感染的研究将提供关键信息 关于病毒-CN相互作用的机制，这些机制将允许更多 针对人类和非人类灵长类动物的专注，知情的调查。 具体的 新生大鼠模型中的目的是：i）表征 行为，认知和运动不足； ii）检查神经病理学 与神经系统异常有关； iii）评估变化 细胞因子的水平是BDV相关损伤的潜在介质； iv） 辨别凋亡是否有助于观察到的神经病理学 新生儿感染和v）评估神经递质的区域变化和 新生儿BDV感染后神经内分泌系统。 具体目标 该应用程序的灵长类动物组成部分是：1）建立非人类 BDV CNS感染的灵长类动物模型使用胎儿和断奶恒河 猕猴； 2）确定体液免疫反应对BDV的时间 在感染的胎儿（子宫内脑室内感染）和断奶 （脑内感染或鼻内感染）猕猴； 3）评估是否 可以在外周白细胞（WBC）中检测到BDV核酸酸 感染的恒河猕猴；如果发现WBC包含BDV 可以在外周白细胞（WBC）或 感染的恒河猕猴；如果发现WBC包含BDV 核酸，确定BDV核酸的分布 尊重感染后的细胞类型和时间； 4）定义 脑脊液（CFS）的血液学，化学和病毒学特征 感染的胎儿和断奶恒河猕猴； 5）表征的性质 任何神经行为，社会情感或运动缺陷，6）评估 通过体内（MRI和PET脑成像）和验尸的神经病理学 分析。