MECHANISMS OF NEUROPATHOGENESIS IN BORNA DISEASE

描述(申请人摘要)：博尔纳病病毒是一种新的 感染温血动物中枢神经系统的分类RNA病毒引起 运动和行为的紊乱。自然感染已被证实 只有马、羊、牛、鸟和猫；然而，灵长类动物可以 实验感染的。尽管这些数据仍然存在争议，但有几个 调查人员已报告有证据表明精神分裂症和 情感障碍。以前对BDV致病机理的大多数工作都集中在 受感染的具有免疫能力的成年啮齿动物和有蹄类动物 行为障碍、边缘回路和单胺类神经递质 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)。虽然这些型号是 耐人寻味的是，它们与中枢神经系统炎症、明显的脑损伤有关 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BDV的大鼠中，BDV引起微妙的 无炎性行为、海马区和小脑发育不全 细胞渗入。该项目的主要目标是：(1) 确定病毒感染改变中枢神经系统结构的机制 并且在不调用浸润性炎症因素的情况下起作用和(2) 建立和研究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一直是 据描述，非人灵长类动物的研究仅在 感染成年恒河猴。这里提出的研究将澄清 灵长类动物可以在围产期被感染，如果是这样， 临床、行为和神经病理后遗症与人类一致 精神疾病。研究人员假设围产期 感染恒河猴将表现为微妙的神经行为和 新生大鼠与灵长类动物对应的神经病理障碍 BDV持续感染模型。他们进一步建议，澄清 这种神经功能障碍的发病机制是通过更广泛的 对新生大鼠BDV感染的研究将提供关键信息 关于病毒-中枢神经系统相互作用的机制，然后将允许 在人类和非人类灵长类动物中进行有重点的、知情的研究。特定的 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 与神经异常有关；iii)评估 细胞因子水平作为BDV相关损害的潜在媒介；iv) 明确细胞凋亡是否参与脑损伤后的神经病理改变 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 这个应用程序的灵长类组件的主要目的是：1)建立非人类 利用胎儿和断奶恒河猴建立BDV中枢感染的灵长类动物模型 猕猴；2)确定BDV体液免疫应答的时程 感染胎儿(宫内脑室感染)和断奶 (脑内或鼻腔感染)恒河猴；3)评估 人外周血白细胞(WBC)中可检测到BDV核酸 受感染的恒河猴；如果发现WBC含有BDV 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，用来确定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)血液学、化学和病毒学特征 感染胎儿和断奶的恒河猴；5)表征 任何神经行为、社会情绪或运动缺陷，并评估 通过活体(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.