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

• 批准号: 10208942
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208942
• 关键词: Acute; Acute Lung Injury; Adolescent; Adult; Adult Respiratory Distress Syndrome; Age; 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; 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 epithelium; alveolar type II cell; base; cell type; chemokine receptor; clinically relevant; comorbidity; design; gamma-Chemokines; in vitro Model; in vivo; influenza infection; 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

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.

项目摘要 K 08提案的广泛目标有两个方面：（1）促进基本科学和技术的发展， 专业技能，使候选人，布里亚科茨博士，实现她的长期目标，成为一个 专注于病毒性肺炎儿童急性肺损伤发展的独立医生-科学家 呼吸道感染和寻求解决方案，可以转化为治疗效益，以危重病 儿童，以及（2）研究调节对甲型流感病毒（IAV）的免疫应答的机制， 导致儿科患者人群的发病率和死亡率增加。通过实验室 经验，教学课程，和合作过程中，博士科茨将获得专业知识，在实验 设计、实验室程序、数据分析和科学交流。科茨博士和她的导师，博士。 凯伦里奇设计了一个具体的培训计划，将提供科茨博士新的知识和研究 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，在年轻的病毒性肺炎患者中引起巨大的发病率和死亡率。 呼吸道感染重要的是，最近的临床数据推翻了长期以来的教条，即儿童 流感由于病毒清除受损而增加了发病率和死亡率。我们的初步数据表明 在IAV感染的幼年小鼠中改变的先天免疫应答作为疾病的关键参数 进展具体地说，我们发现，在IAV感染的幼年小鼠中，肺损伤的增加与 NOD样受体（NLR）蛋白NOD 2和NLRP 3的强烈激活，导致IFNα/β增加 和IL-1β/18水平，持续超过病毒消除。此外，青少年的肺产生更多的 在IAV感染期间，MCP-1和招募更多的炎性单核细胞，然后使NOD 2和 NLRP 3激活。我们观察到幼年募集的单核细胞是唯一的炎症细胞， 它们在IAV感染期间的募集保护幼年小鼠免受IAV介导的肺损伤。我们假设 年龄特异性，细胞自主差异的先天免疫反应，以IAV有助于 NLR蛋白的持续激活并加重IAV诱导的青少年肺损伤 小鼠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的调节， 幼年IAV诱导的肺损伤的体内和体外模型中的NLR信号传导。具体目标1： 研究年龄特异性调节IAV应答中NLR蛋白激活的机制 感染并导致IAV诱导急性肺损伤。具体目标2：确定是否招募 单核细胞是幼年小鼠中IAV介导的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，并揭示其机制 小儿病毒性呼吸道感染致急性肺损伤。