PERSISTENCE OF DISEASE VIRUS IN ASTROCYTES

星形胶质细胞中疾病病毒的持续存在

基本信息

批准号：
3478067
负责人：
KATHRYN M. CARBONE
金额：
$ 9.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-01 至 1995-07-31
项目状态：
已结题

项目摘要

Borna disease virus (BDV) replicates only in the nervous system and produces a persistent, productive infection. This molecularly uncharacterized agent infects a wide range of species, from chimpanzees to chickens, and is identified by a unique virus associated antigen. A similar virus has been identified in patients with neurological and psychiatric illnesses (eg. schizophrenia, manic depressive disorders). Disease expression in Borna disease ranges from social behavioral abnormalities in tupiais to fatal encephalomyelitis in its natural hosts, horses and sheep. BDV infection in the rat is one of only a few models of chronic viral encephalitis. In rats, the first signs of Borna disease are aggression and ataxia (acute disease), followed by listlessness and hypoactivity (chronic disease). The surviving animals remain in the chronic disease state for life. In acute disease there is a transient, necrotizing encephalitis and an associated loss of infected neurons. Subsequently, resolution of inflammation occurs despite increasing numbers of BDV-infected glial cells (eg. astrocytes). Neonatally inoculated rats become persistently infected but develop no signs of disease or inflammation (persistent, tolerant infection or PTI). Preliminary data reveal that MHC I and II expression also persists in chronic disease, even after the resolution of inflammation. This proposal will investigate 1. The mechanisms of destruction of infected neurons and sparing of infected glial cells, and 2. The relationship of these events to the decline in inflammation during chronic Borna disease. 1. MHC I and II expression in the BDV-infected nervous system will be described. Individual neural cells expressing MHC (eg. infected neurons, astrocytes, and Schwann cells) will be identified using double label immunohistochemistry and one micron thick serial sections. Tissue sections from BDV-infected rats with encephalitis, post-encephalitis, and no encephalitis (PTI) will be stained with cell, BDV antigen and MHC specific antibodies 2. Infected astrocytes from rats in each stage of disease will be cultured and examined in vitro for modulation of MHC I and II expression. these astrocytes will be tested for loss of disease. BDV antigen-specific T cell lines have been developed to serve as effector cells in these assays. Through parabiosis (surgically joined rats which share a common immune system), an in vivo model is available to determine whether the inflammatory cells from a rat with acute disease respond to the BDV infected neural cells of a rat with chronic disease or PTI by producing inflammation or disease.

博尔纳病病毒 (BDV) 仅在神经系统中复制产生持续性、生产性感染。这种分子未知病原体感染多种物种，从黑猩猩到鸡，并通过独特的病毒相关抗原进行识别。一个在患有神经系统疾病和疾病的患者中也发现了类似的病毒精神疾病（例如精神分裂症、躁狂抑郁症）。博尔纳病的疾病表现范围包括社会行为兔兔的异常在其自然宿主中导致致命性脑脊髓炎，马和羊。大鼠 BDV 感染是仅有的几种模型之一慢性病毒性脑炎。在大鼠中，博尔纳病的第一个迹象是攻击性和共济失调（急性疾病），随后是无精打采和活动减退（慢性疾病）。幸存的动物仍留在终生慢性疾病状态。在急性疾病中，存在短暂的、坏死性脑炎和相关的受感染神经元损失。随后，尽管数量不断增加，炎症仍会消退 BDV 感染的神经胶质细胞（例如星形胶质细胞）。新生接种大鼠持续感染但没有出现疾病迹象或炎症（持续性、耐受性感染或 PTI）。初步数据揭示 MHC I 和 II 表达在慢性疾病中也持续存在，甚至炎症消退后。本提案将调查 1。破坏受感染神经元和保留受感染神经元的机制神经胶质细胞，以及 2. 这些事件与神经胶质细胞下降的关系慢性博尔纳病期间的炎症。 1. MHC I 和 II 的表达将描述BDV感染的神经系统。单个神经细胞表达 MHC（例如受感染的神经元、星形胶质细胞和施万细胞）将使用双标记免疫组织化学和一微米厚进行鉴定连续部分。感染 BDV 的脑炎大鼠的组织切片，脑炎后，无脑炎（PTI）会被细胞、BDV染色抗原和 MHC 特异性抗体 2. 来自大鼠的感染星形胶质细胞疾病的每个阶段都将在体外进行培养和检查以进行调节 MHC I 和 II 表达。将测试这些星形胶质细胞的损失疾病。 BDV 抗原特异性 T 细胞系已被开发用作这些测定中的效应细胞。通过联体共生（手术连接老鼠它们共享共同的免疫系统），体内模型可用于确定炎症细胞是否来自患有急性疾病的大鼠对患有慢性疾病的大鼠的 BDV 感染的神经细胞做出反应，或 PTI 通过产生炎症或疾病。