RSV-induced inflammation in the brain

摘要 呼吸道合胞病毒(RSV)是一种高度传染性的肺炎病毒，70%以上的儿童感染 一岁的儿童和两岁前几乎100%的儿童。由于产生的免疫记忆不佳 在疾病解决后，RSV产生反复爆发的感染，有助于病毒在 社区。呼吸道合胞病毒会产生各种临床表现，从鼻炎和中耳炎到更多 肺炎和毛细支气管炎等严重疾病。除了呼吸道合胞病毒引起的呼吸道疾病外， 临床报告描述了大约2%的呼吸道合胞病毒感染者出现神经症状。 孩子们。由于大多数儿童每年都会感染呼吸道合胞病毒，这部分受感染的人口可能 代表了相当数量的病人。神经系统症状包括非发热性癫痫，中枢性呼吸暂停， 嗜睡、进食/吞咽困难、肌张力异常、斜视、脑脊液fl 脑部病变和脑病。支持这些观察结果的是，使用 小鼠呼吸道合胞病毒感染模型，包括证明合胞病毒引起病毒血症和病毒感染 神经系统(CNS)。引人注目的是，感染RSV的小鼠和大鼠都表现出学习和行为上的改变。 在感染一个月后。我们已经描述了感染RSV的小鼠已经改变了血脑屏障 血脑屏障(BBB)通透性，表现为大脑和中枢神经系统细胞中炎性细胞浸润增加，如 星形胶质细胞，被RSV主动感染。考虑到儿童感染RSV的负担，这样的发现是 对公共卫生的高度关注。然而，引起RSV的病理生理机制 中枢神经系统的扩散和认知/行为表现尚不清楚。我们相信， 呼吸道合胞病毒感染在肺部引发的炎症反应类型有利于中枢神经系统的发展 改装。我们的研究表明，RSV能够感染中枢神经系统，促进认知/行为 血脑屏障(BBB)通透性改变引起的损害。因此，BBB的开业 可能会让呼吸道合胞病毒和/或炎症细胞渗入大脑。根据这些观察，我们的中央 假设是RSV感染引起的炎症反应会导致神经系统的改变 通过增加血脑屏障的通透性，炎症细胞向中枢神经系统募集和感染 神经细胞。这笔赠款的具体目标是研究呼吸道合胞病毒感染的病理过程及其 对中枢神经系统的影响。这将通过确定BBB的结构和功能变化来实现 在RSV感染后，鉴定被RSV感染的脑细胞及其感染动力学 在老鼠身上。这项研究的结果将有助于更好地理解神经病理所引起的 通过呼吸道合胞病毒和可能对人类中枢神经系统的有害影响。此外，对人类的了解 调节RSV脑感染机制及其宿主炎症反应可产生新的 可帮助预防呼吸道合胞病毒通过中枢神经系统感染的后果的工具。

ABSTRACT Respiratory syncytial virus (RSV) is a highly contagious pneumovirus that infects over 70% of children under one year of age and nearly 100% of children by age two. Due to the poor immunological memory generated after disease resolution, RSV produces recurrent outbreaks of infection that contribute to viral dissemination in the community. RSV produces various clinical manifestations, ranging from rhinitis and otitis media, to more severe diseases such as pneumonia and bronchiolitis. In addition to the respiratory disease caused by RSV, clinical reports have described the development of neurological symptoms in around 2% of RSV-infected children. Since most children get infected by RSV every year, this fraction of the infected population can represent a significant number of patients. Neurological symptoms include non-febrile seizures, central apnea, lethargy, feeding/swallowing difficulties, muscular tone abnormalities, strabismus, cerebrospinal fluid (CSF) alterations and encephalopathy. Supporting these observations, similar results have been obtained using the murine model of RSV infection including the demonstration that RSV causes viremia and infection of the nervous system (CNS). Strikingly, RSV infected mice and rats show both learning and behavioral alterations after one month of infection. We have described that mice infected by RSV have altered blood brain barrier (BBB) permeability, exhibit increased infiltration of inflammatory cells in the brain and CNS cells, such as astrocytes, are actively infected by RSV. Considering the burden of RSV-infection in children, such a finding is of high interest for public health. However, the pathophysiological mechanisms responsible for RSV dissemination into the CNS and the cognitive/behavioral manifestations remain unknown. We believe that the type of inflammatory response triggered by RSV infection in the lungs favors the development of the CNS alterations. Our studies suggest that RSV is able to infect the CNS and promote cognitive/behavioral impairment due to the alteration of the blood brain barrier (BBB) permeability. Thus, the opening of the BBB could allow RSV and/or the inflammatory cells to infiltrate the brain. Based on these observations, our central hypothesis is that the inflammatory response elicited by RSV infection leads to neurological alterations caused by increased permeability of the BBB, the recruitment of inflammatory cells to the CNS and the infection of nerve cells. The specific aims of this grant will address the pathological processes of RSV infection and its effects on the CNS. This will be achieved by determining the structural and functional changes at the BBB following RSV infection and identifying the brain cells that are infected by RSV, as well as its infection kinetics in mice. The results obtained in this proposal will provide a better understanding of the neuropathology caused by RSV and the possible detrimental effects at the CNS in humans. Moreover, the knowledge of the modulation of the mechanism of RSV brain infection and its host inflammatory response could generate new tools that can help to prevent the consequences of RSV infection over the CNS.