MECHANISMS OF NEUROPATHOGENESIS IN BORNA DISEASE

描述（申请人的摘要）：博尔纳病病毒（BDV）是一种新的 一种分类的RNA病毒，感染温血动物的中枢神经系统， 运动和行为障碍。 已确认自然感染 只有在马，羊，牛，鸟和猫;然而，灵长类动物可以 实验性感染 尽管这些数据仍然存在争议，但一些 研究人员已经报道了精神分裂症感染的证据， 情感障碍 以前在BDV发病机制方面的大多数工作都集中在 感染的成年免疫活性啮齿动物和有蹄类动物， 行为、边缘系统回路和单胺神经递质紊乱 这些系统让人联想到一些神经精神综合征的某些方面， （自闭症、精神分裂症或双相情感障碍）。 虽然这些模型 有趣的是，它们与中枢神经系统炎症有关， 肿块和胶质增生，可能与神经精神疾病的相关性低于 在BDV诱导轻微干扰的腹腔感染大鼠中， 行为，海马和小脑发育不全，无炎症 细胞浸润 本项目的总体目标是：（1） 确定病毒感染改变CNS结构的机制 和功能，而不引起浸润性炎症因子和（2） BDV非人灵长类动物感染模型的建立和研究。 然而，新生大鼠持续耐受性感染的模型已经被证明是有效的。 描述，非人类灵长类动物的研究已经进行了只有在急性 感染的成年恒河猴。 本文提出的研究将澄清， 灵长类动物可以在围产期感染，如果是这样， 临床、行为和神经病理学后遗症与人类 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 与新生大鼠相似的灵长类动物的神经病理学紊乱 持续BDV感染模型。 他们进一步建议， 这种神经功能障碍的发病机制通过更广泛的 新生大鼠BDV感染的研究将提供关键信息 关于病毒与中枢神经系统相互作用的机制， 在人类和非人类灵长类动物中进行的有针对性的知情调查。 具体 新生大鼠模型的目的是：i）表征 行为、认知和运动缺陷; ii）检查神经病理学 与神经系统异常相关; iii）评估 作为BVDV相关损伤的潜在介质的细胞因子水平; iv） 辨别细胞凋亡是否有助于观察后的神经病理学 新生儿感染和v）评估神经递质的区域变化， 新生儿BDV感染后的神经内分泌系统。 具体目标 本申请的灵长类动物组分的主要目的是：1）建立非人的 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）确定对BDV的体液免疫应答的时程 感染胎儿（子宫内脑室内感染）和断奶 （脑内或鼻内感染）恒河猴; 3）评估是否 BDV核酸可以在外周白色血细胞（WBC）中检测到， 感染的恒河猴;如果发现WBC含有BDV 可以在外周白色血细胞（WBC）或外周血淋巴细胞（PBMC）中检测核酸。 感染的恒河猴;以及如果发现WBC含有BDV 核酸，以确定BDV核酸的分布， 关于细胞类型和感染后的时间进程; 4）定义 脑脊液（CFS）血液学、化学和病毒学特征 感染的胎儿和断奶恒河猴; 5）表征的性质 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）和死后的神经病理学 分析。

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.