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

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病毒，可感染 70% 以上的儿童 一岁和近 100% 的儿童在两岁时由于免疫记忆较差而发生这种情况。 疾病消退后，RSV 会反复爆发感染，导致病毒在体内传播 RSV 会产生各种临床表现，包括鼻炎和中耳炎等。 除RSV引起的呼吸道疾病外，还包括肺炎和细支气管炎等严重疾病。 临床报告描述了约 2% 的 RSV 感染者出现神经系统症状 由于每年大多数儿童都会感染 RSV，因此这部分感染者可能会感染 RSV。 代表了大量患者的神经系统症状，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) 支持这些观察结果，使用以下方法获得了类似的结果。 RSV 感染的小鼠模型，包括证明 RSV 引起病毒血症和感染 引人注目的是，RSV 感染的小鼠和大鼠表现出学习和行为改变。 我们已经描述了感染RSV的小鼠在感染1个月后出现了血脑屏障。 (BBB)渗透性，表现出大脑和中枢神经系统细胞中炎症细胞浸润增加，例如 考虑到儿童 RSV 感染的负担，这一发现是正确的。 然而，RSV 的病理生理机制引起了公众的高度关注。 我们认为，传播到中枢神经系统和认知/行为表现仍然未知。 RSV 感染引发的肺部炎症反应有利于中枢神经系统的发育 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伤，因此，BBB的开放。 根据这些观察，我们的中枢可能会允许 RSV 和/或炎症细胞渗入大脑。 假设是 RSV 感染引起的炎症反应会导致神经系统改变 通过增加血脑屏障的通透性、向中枢神经系统募集炎症细胞以及感染 此项资助的具体目标是解决 RSV 感染的病理过程及其相关问题。 这将通过确定 BBB 的结构和功能变化来实现。 RSV 感染后并识别被 RSV 感染的脑细胞及其感染动力学 在小鼠中获得的结果将有助于更好地理解引起的神经病理学。 RSV 以及对人类中枢神经系统可能造​​成的痛苦影响。 调节 RSV 脑部感染机制及其宿主炎症反应可能会产生新的 有助于预防 RSV 感染对中枢神经系统造成后果的工具。