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，感染70%以上的儿童， 一岁的孩子和两岁的孩子几乎100%。由于免疫记忆差， 在疾病消退后，RSV会引起感染的复发性爆发，导致病毒传播， 社会各界RSV产生各种临床表现，范围从鼻炎和中耳炎， 严重的疾病，如肺炎和细支气管炎。除了RSV引起的呼吸道疾病外， 临床报告描述了约2%的RSV感染者出现神经系统症状， 孩子由于大多数儿童每年都会感染RSV，因此这部分感染人群可以 代表了相当多的患者。神经系统症状包括非热性惊厥，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（CSF） 改变和脑病。支持这些观察结果，使用 RSV感染的小鼠模型，包括RSV引起病毒血症和病毒感染的证明 神经系统（CNS）。引人注目的是，RSV感染的小鼠和大鼠表现出学习和行为的改变 感染一个月后。我们已经描述了RSV感染的小鼠改变了血脑屏障， (BBB)渗透性，表现出脑和CNS细胞中炎性细胞的浸润增加，例如 星形胶质细胞被RSV主动感染。考虑到儿童RSV感染的负担，这一发现是 对公共卫生有很高的兴趣。然而，RSV的病理生理机制 传播到CNS和认知/行为表现仍然未知。我们认为 由RSV感染引发的肺部炎症反应类型有利于CNS的发展 改变。我们的研究表明，RSV能够感染CNS并促进认知/行为 由于血脑屏障（BBB）通透性的改变而导致的损害。因此，BBB的开放 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 一种假说是RSV感染引起的炎症反应导致神经系统改变， 通过增加血脑屏障的渗透性，炎症细胞向中枢神经系统的募集和感染， 神经细胞该基金的具体目标是解决RSV感染的病理过程及其 对CNS的影响。这将通过确定BBB的结构和功能变化来实现 在RSV感染后并鉴定被RSV感染的脑细胞，以及其感染动力学 对小鼠在这项建议中获得的结果将提供一个更好的理解神经病理学引起的 RSV和可能对人类中枢神经系统的有害影响。此外， RSV脑感染及其宿主炎症反应机制的调节可以产生新的 这些工具可以帮助预防RSV感染对CNS造成的后果。

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.