RSV-induced inflammation in the brain

RSV 诱发的大脑炎症

• 批准号: 10252048
• 负责人: Steven M Varga
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252048
• 关键词: 1 year old; 2 year old; Acute; Address; Affect; Age; Alveolitis; Animals; Antibodies; Astrocytes; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Bronchiolitis; Cells; Central Nervous System Diseases; Central Sleep Apnea; Cerebrospinal Fluid; Cessation of life; Child; Clinical; Cognition; Cognitive; Communities; Control Animal; Data; Deglutition; Development; Disease; Disease Outbreaks; Emergency department visit; Encephalopathies; Exhibits; Genetic Materials; Goals; Grant; Hospitalization; Human; Immune response; Immunologic Memory; Impaired cognition; Infant; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Kinetics; Knowledge; Learning; Lethargies; Lower Respiratory Tract Infection; Lung; Lung diseases; Lung infections; Molecular; Mus; Muscle; Nerve Tissue; Neurologic; Neurologic Symptoms; Neurons; Otitis Media; Outpatients; Pathologic Processes; Patients; Play; Pneumonia; Pneumovirus; Population; Private Practice; Public Health; Rattus; Recurrence; Reporter; Reporting; Resolution; Respiration; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Rhinitis; Role; Seasons; Strabismus; Structure; Testing; Viral; Viremia; Virus; Virus Diseases; Visit; World Health Organization; base; behavioral impairment; blood-brain barrier permeabilization; brain cell; brain tissue; cognitive process; cytokine; design; epidemiology study; experimental study; feeding; insight; interest; learned behavior; lung injury; mouse model; nervous system infection; neuropathology; prevent; recruit; symptomatology; tool; virus genetics; 1 year old; 2 year old; Acute; Address; Affect; Age; Alveolitis; Animals; Antibodies; Astrocytes; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Bronchiolitis; Cells; Central Nervous System Diseases; Central Sleep Apnea; Cerebrospinal Fluid; Cessation of life; Child; Clinical; Cognition; Cognitive; Communities; Control Animal; Data; Deglutition; Development; Disease; Disease Outbreaks; Emergency department visit; Encephalopathies; Exhibits; Genetic Materials; Goals; Grant; Hospitalization; Human; Immune response; Immunologic Memory; Impaired cognition; Infant; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Kinetics; Knowledge; Learning; Lethargies; Lower Respiratory Tract Infection; Lung; Lung diseases; Lung infections; Molecular; Mus; Muscle; Nerve Tissue; Neurologic; Neurologic Symptoms; Neurons; Otitis Media; Outpatients; Pathologic Processes; Patients; Play; Pneumonia; Pneumovirus; Population; Private Practice; Public Health; Rattus; Recurrence; Reporter; Reporting; Resolution; Respiration; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Rhinitis; Role; Seasons; Strabismus; Structure; Testing; Viral; Viremia; Virus; Virus Diseases; Visit; World Health Organization; base; behavioral impairment; blood-brain barrier permeabilization; brain cell; brain tissue; cognitive process; cytokine; design; epidemiology study; experimental study; feeding; insight; interest; learned behavior; lung injury; mouse model; nervous system infection; neuropathology; prevent; recruit; symptomatology; tool; virus genetics

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.

抽象的 呼吸道合胞病毒（RSV）是一种高度传染性的肺炎病毒，感染了超过70％的儿童 一岁，几乎是两岁的儿童。由于产生的免疫记忆不佳 疾病解决后，RSV会产生反复发出的感染爆发，导致病毒传播 社区。 RSV产生各种临床表现，从鼻炎和中耳炎到更多 严重的疾病，例如肺炎和细支气管炎。除了由RSV引起的呼吸道疾病外， 临床报告描述了大约2％的RSV感染的神经系统症状的发展 孩子们。由于大多数儿童每年都会感染RSV，因此感染人群中的这一部分可以 代表大量患者。神经系统症状包括非脑癫痫发作，中央呼吸暂停， 嗜睡，喂食/吞咽困难，肌肉色调异常，斜视，脑脊液（CSF） 改变和脑病。支持这些观察结果，使用 RSV感染的鼠模型，包括RSV引起病毒血症和感染的演示 神经系统（CNS）。令人惊讶的是，RSV感染的小鼠和大鼠既显示学习和行为改变 感染了一个月后。我们已经描述了被RSV感染的小鼠已经改变了血脑屏障 （BBB）渗透性，暴露于大脑和CNS细胞中炎症细胞的浸润增加，例如 星形胶质细胞被RSV积极感染。考虑到儿童RSV感染的燃烧，这样的发现是 对公共卫生的兴趣很高。但是，负责RSV的病理生理机制 传播到中枢神经系统中，认知/行为表现仍然未知。我们相信 RSV感染引发的炎症反应类型有利于CNS的发展 改变。我们的研究表明，RSV能够感染中枢神经系统并促进认知/行为 由于血脑屏障（BBB）渗透性的改变而导致的损害。那是BBB的开放 可以允许RSV和/或炎性细胞浸润大脑。基于这些观察，我们的中心 假设是RSV感染引起的炎症反应导致神经系统改变引起 通过增加BBB的渗透性，炎症细胞募集到中枢神经系统的感染和感染 神经细胞。这笔赠款的具体目的将解决RSV感染的病理过程 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 遵循RSV感染并识别由RSV感染的脑细胞及其感染动力学 在老鼠中。本提案中获得的结果将更好地理解引起的神经病理学 通过RSV以及人类中枢神经系统的可能有害影响。而且，知识 调节RSV脑感染机制及其宿主炎症反应可能会产生新的 可以帮助防止CNS感染RSV感染后果的工具。