MECHANISMS OF NEUROPATHOGENESIS IN BORNA DISEASE

博尔纳病的神经发病机制

• 批准号: 2889947
• 负责人: MADY HORNIG
• 金额: $ 15.03万
• 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/2889947
• 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（申请人摘要）：博尔纳病病毒（BDV）是一种新的 分类RNA病毒，感染温血动物的中枢神经系统，导致 运动和行为障碍。 已确认自然感染 仅存在于马、羊、牛、鸟和猫中；然而，灵长类动物可以 实验性感染。 尽管数据仍存在争议，但一些 研究人员报告了精神分裂症感染的证据 情感障碍。 BDV 发病机制的大部分先前工作都集中在 感染的成年免疫活性啮齿动物和有蹄类动物的情况非常严重 行为、边缘回路和单胺神经递质紊乱 系统让人想起一些神经精神综合症的各个方面 （自闭症、精神分裂症或双相情感障碍）。 虽然这些模型是 有趣的是，它们与中枢神经系统炎症、大脑明显丧失有关 肿块和神经胶质增生，与神经精神疾病的相关性可能不如 在新生感染的大鼠中，BDV 会引起微妙的紊乱 行为、海马和小脑发育不全，无炎症 细胞浸润。 该项目的总体目标是：(1) 确定病毒感染改变中枢神经系统结构的机制 和功能而不引起浸润的炎症成分和（2） 建立并研究 BDV 感染的非人灵长类动物模型。 而新生大鼠持续耐受感染的模型已 据描述，非人类灵长类动物研究仅在严重的情况下进行 感染的成年恒河猴。 这里提出的研究将澄清是否 灵长类动物可能在围产期被感染，如果是的话，是否 临床、行为和神经病理学后遗症与人类一致 精神疾病。 研究人员推测围产期 恒河猴的感染会表现为微妙的神经行为和 与新生大鼠对应的灵长类动物的神经病理学紊乱 持续性 BDV 感染模型。 他们进一步建议澄清 通过更广泛的研究来了解这种神经功能障碍的发病机制 大鼠新生 BDV 感染研究将提供重要信息 关于病毒与中枢神经系统相互作用的机制，这将允许更多 对人类和非人类灵长类动物进行有针对性的、知情的调查。 具体的 新生大鼠模型的目标是： i) 描述新生大鼠模型的性质 行为、认知和运动缺陷； ii) 检查神经病理学 与神经系统异常有关； iii) 评估变化 作为 BDV 相关损伤潜在介质的细胞因子水平；四） 辨别细胞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 感染后的神经内分泌系统。 具体目标 该应用程序的灵长类成分是：1）建立非人类 使用胎儿和断奶恒河猴建立 BDV CNS 感染的灵长类动物模型 猕猴； 2）确定BDV体液免疫反应的时间进程 在受感染的胎儿（子宫内脑室内感染）和断奶时 （脑内或鼻内感染）恒河猴； 3）评估是否 BDV 核酸可在外周血白细胞 (WBC) 中检测到 受感染的恒河猴；如果发现 WBC 含有 BDV 核酸可以在外周血白细胞（WBC）或 受感染的恒河猴；如果发现 WBC 含有 BDV 核酸，以确定 BDV 核酸的分布 关于感染后的细胞类型和时间进程； 4）定义 脑脊液 (CFS) 的血液学、化学和病毒学特征 受感染的胎儿和断奶恒河猴； 5) 描述性质 任何神经行为、社会情感或运动缺陷，以及 6) 评估 通过体内（MRI 和 PET 脑成像）和尸检进行神经病理学 分析。