Pathophysiology of Influenza A Virus-induced Lung Injury in Juveniles

甲型流感病毒引起的青少年肺损伤的病理生理学

基本信息

批准号：
9756467
负责人：
Bria M Coates
金额：
$ 16.12万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756467
关键词：
Acute Acute Lung Injury Adolescent Adult Adult Respiratory Distress Syndrome Age Alveolar Alveolar Macrophages Animal Model Antibodies Antiviral Agents Antiviral Response Antiviral Therapy Automobile Driving CCL2 gene CCR1 gene Cell model Cells Cessation of life Child Childhood Childhood Injury Clinical Clinical Data Communication Coupled Critically ill children Data Data Analyses Development Disease Disease Progression Epidemic Epithelial Cells Equilibrium Experimental Designs Expression Profiling Fostering Functional disorder Gene Expression Goals IRF3 gene ITGAX gene Immune response Immunologic Memory Impairment Infection Infection Control Inflammasome Inflammatory Inflammatory Response Influenza Influenza A virus Innate Immune Response Interferon-alpha Interferon-beta Interleukin-1 beta Interleukin-18 Intervention Knowledge Laboratory Procedures Life Lung Lung Inflammation Mediating Medical Mentors Morbidity - disease rate Mus Pathogenesis Pathway interactions Patients Peripheral Physicians Pneumonia Population Prevention Process Production Receptor Activation Receptor Signaling Regulation Research Respiratory Tract Infections Risk Role Scientist Signal Transduction Supportive care Testing Therapeutic Tissues Training Training Programs Translating Viral Viral Pneumonia Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Vulnerable Populations alveolar type II cell base cell type chemokine receptor clinically relevant design gamma-Chemokines in vitro Model in vivo laboratory experience lung development lung injury mature animal monocyte monocyte chemoattractant protein 1 receptor mortality mouse model novel novel therapeutics pandemic disease patient population pediatric patients prevent receptor receptor expression recruit response skills tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY The broad objectives of this K08 proposal are two-fold: (1) to foster the development of essential scientific and professional skills that will allow the candidate, Dr. Bria Coates, to achieve her long-term goal of becoming an independent physician-scientist concentrating on the development of acute lung injury in children with viral respiratory infections and seeking solutions that could be translated for therapeutic benefit to critically ill children, and (2) to investigate mechanisms that regulate the immune response to influenza A virus (IAV) and contribute to increased morbidity and mortality in the pediatric patient population. Through laboratory experience, didactic coursework, and the collaborative process, Dr. Coates will gain expertise in experimental design, laboratory procedures, data analysis, and scientific communication. Dr. Coates and her mentor, Dr. Karen Ridge, have designed a specific training plan that will afford Dr. Coates new knowledge and research skills in the pathophysiology of acute lung inflammation and acute respiratory distress syndrome (ARDS), which is a lung condition that causes tremendous morbidity and mortality in young patients with viral respiratory infections. Importantly, recent clinical data thwart the long-standing dogma that children with influenza have increased morbidity and mortality due to impaired viral clearance. Our preliminary data identify an altered innate immune response in IAV-infected juvenile mice as a critical parameter in disease progression. Specifically, we show that increased lung injury in IAV-infected juvenile mice is associated with robust activation of the NOD-like receptor (NLR) proteins NOD2 and the NLRP3, resulting in increased IFNα/β and IL-1β/18 levels, respectively, that persist beyond viral elimination. In addition, juvenile lungs produce more MCP-1 and recruit more inflammatory monocytes during IAV infection, which then perpetuates NOD2 and NLRP3 activation. We observe that juvenile recruited monocytes are uniquely inflammatory, and prevention of their recruitment during IAV infection protects juvenile mice from IAV-mediated lung injury. We hypothesize that age-specific, cell autonomous differences in the innate immune response to IAV contribute to the robust and sustained activation of NLR proteins and exacerbate IAV-induced lung injury in juvenile mice. We have formulated three interrelated specific aims to study the regulation of monocyte recruitment and NLR signaling in both in vivo and in vitro models of juvenile IAV-induced lung injury. Specific Aim 1: Investigate the age-specific mechanisms that modulate the activation of NLR proteins in response to IAV infection and contribute to IAV-induced acute lung injury. Specific Aim 2: Determine whether recruited monocytes are required for IAV-mediated acute lung injury in juvenile mice. Specific Aim 3: Identify cell autonomous differences in juvenile IAV infection that may drive age-specific inflammatory responses. Completion of these aims will provide a rigorous training program for Dr. Coates and uncover mechanisms driving acute lung injury in children with viral respiratory infections.

项目概要 K08 提案的广泛目标有两个：(1) 促进基本科学和技术的发展专业技能将使候选人 Bria Coates 博士能够实现成为一名独立医师科学家，专注于病毒感染儿童急性肺损伤的发展呼吸道感染并寻求可以转化为危重病人治疗效果的解决方案儿童，(2) 研究调节甲型流感病毒 (IAV) 免疫反应的机制和通过实验室，导致儿科患者发病率和死亡率增加。经验、教学课程和协作过程，科茨博士将获得实验方面的专业知识设计、实验室程序、数据分析和科学交流。 Karen Ridge 设计了一个具体的培训计划，为 Coates 博士提供新的知识和研究急性肺部炎症和急性呼吸窘迫综合征（ARDS）的病理生理学技能，这是一种肺部疾病，会导致年轻病毒感染者发病率和死亡率极高重要的是，最近的临床数据打破了长期以来认为儿童患有呼吸道感染的教条。我们的初步数据表明，由于病毒清除受损，流感的发病率和死亡率增加。感染 IAV 的幼年小鼠先天免疫反应的改变是疾病的关键参数具体来说，我们发现感染 IAV 的幼年小鼠的肺损伤增加与 NOD 样受体 (NLR) 蛋白 NOD2 和 NLRP3 的强烈激活，导致 IFNα/β 增加和 IL-1β/18 水平分别在病毒消除后持续存在。此外，幼年肺部产生更多。 MCP-1 并在 IAV 感染期间招募更多炎症单核细胞，从而使 NOD2 和我们观察到幼年募集的单核细胞具有独特的炎症性，并且可以预防它们在 IAV 感染期间的募集可以保护幼年小鼠免受 IAV 介导的肺损伤。年龄特异性、细胞自主性对 IAV 的先天免疫反应的差异有助于 NLR 蛋白的强烈和持续激活并加剧 IAV 引起的青少年肺损伤我们制定了三个相互关联的具体目标来研究单核细胞募集和的调节。幼年 IAV 诱导的肺损伤体内和体外模型中的 NLR 信号传导具体目标 1：研究调节 NLR 蛋白响应 IAV 激活的年龄特异性机制感染并导致 IAV 引起的急性肺损伤具体目标 2：确定是否招募。单核细胞是 IAV 介导的幼年小鼠急性肺损伤所必需的。具体目标 3：识别细胞。青少年 IAV 感染的自主差异可能会驱动年龄特异性炎症反应。完成这些目标将为科茨博士提供严格的培训计划并揭示机制导致患有病毒性呼吸道感染的儿童发生急性肺损伤。