Specialized Pro-Resolving Mediator Regulation of NK Cells in Human RSV Bronchiolitis

人 RSV 毛细支气管炎中 NK 细胞的专门促解介体调节

• 批准号: 10228023
• 负责人: Melody G. Duvall
• 金额: $ 17.27万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228023
• 关键词: Active Sites; Acute; Address; Adopted; Adrenal Cortex Hormones; Advisory Committees; Antiviral Agents; Apoptosis; Area; Autologous; Bronchiolitis; Cell physiology; Cells; Cessation of life; Child; Childhood; Clinical; Confocal Microscopy; Critically ill children; Cytoplasmic Granules; Data; Development Plans; Disease; Ensure; Epithelial Cells; Equilibrium; Essential Fatty Acids; FCGR3B gene; FPR2 gene; Flow Cytometry; Foundations; Gene Expression Profile; Goals; Health; Homeostasis; Hospitalization; Host Defense; Human; Hypoxemia; Immune; Immunobiology; Immunologics; Impairment; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Knowledge; Lead; Leukocytes; Lung; Lytic; Mediator of activation protein; Mentors; Mentorship; Molecular; Molecular Profiling; Molecular Target; NCAM1 gene; NK Cell Activation; Natural Killer Cells; Pathway interactions; Phase; Phenotype; Physicians; Plasma; Pneumonia; Process; Production; Pulmonary Inflammation; Regulation; Research; Research Project Grants; Resolution; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Sampling; Scientist; Severity of illness; Signal Transduction; Technical Expertise; Testing; Time; Tissue-Specific Gene Expression; Tissues; Training; Translational Research; Viral; Virus; Virus Diseases; Wheezing; airway inflammation; career; career development; cytokine; cytotoxic; experimental study; illness length; immunological synapse; lipoxin A4; microscopic imaging; neutrophil; new therapeutic target; novel therapeutics; pediatric patients; receptor; receptor expression; recruit; respiratory; response; skill acquisition; trafficking; transcriptome sequencing; transcriptomics

Project Summary Respiratory syncytial virus (RSV) is the major cause of bronchiolitis in pediatric patients and the leading cause for hospitalization of infants. A subset of RSV-infected children develops overwhelming inflammation that leads to respiratory failure and even death but the immunobiology underlying this severe phenotype of RSV disease is incompletely understood. We have found that natural killer (NK) cells are abundant in the airways of RSV- infected children who have profound inflammation and hypoxemia relative to those with less severe disease. NK cells are pivotal innate mediators of viral host defense and have important functions in both promoting and resolving inflammation. NK cells secrete cytokines to recruit leukocytes to sites of active infection but are also critical effectors of inflammation resolution to later clear activated leukocytes from inflamed tissues to restore homeostasis. Thus, a balance in the pro-inflammatory and pro-resolving features of NK cells is essential to both ensure host defense as well as the appropriate resolution of inflammation. Resolution of inflammation is an active process orchestrated by specialized pro-resolving mediators (SPMs), mediators derived from essential fatty acids that restrain acute inflammatory responses and signal for resolution, in part by influencing NK cell function. In work in progress for this proposal, we have found that human NK cells express four distinct receptors for SPMs and that the SPM lipoxin A4 enhances NK cell resolution functions. We propose a translational research project to study airway and circulating NK cells in children with severe RSV bronchiolitis to understand why the natural “braking” signals (i.e. SPMs) are ineffective at controlling virus-induced inflammation. Our central hypothesis is that the resolution functions of airway NK cells are defective in severe RSV infection contributing to unrestrained inflammation and are targets for reprogramming by SPMs to promote resolution. To test this hypothesis, we propose two specific aims: 1) to identify the NK cell molecular signature associated with severe RSV disease and 2) to determine the impact of SPMs on NK cell resolution function. We will utilize human pediatric samples from children with RSV-associated respiratory failure to address these aims. With the guidance and mentorship of Dr. Bruce Levy, Dr. Duvall has developed a four- year career development plan to provide the mentored research, technical skill development, and tailored didactic training needed to achieve her goal of becoming an independent physician-scientist. Importantly, this project will be overseen by a scientific advisory committee with expertise in the study of pulmonary inflammation, transcriptomic analysis of immune cells, and the effects of SPMs on inflammation resolution, three key areas of this proposal. This proposal will therefore provide the scientific training and career development skills to lay the foundation for Dr. Duvall to become an independent physician-scientist focused on human immune pathways that resolve infectious airway inflammation.

项目概要 呼吸道合胞病毒（RSV）是引起儿童毛细支气管炎的主要原因，也是导致毛细支气管炎的主要原因 用于婴儿住院治疗。一部分感染 RSV 的儿童会出现严重的炎症，导致 呼吸衰竭甚至死亡，但这种严重 RSV 疾病表型背后的免疫生物学 是不完全理解的。我们发现 RSV 呼吸道中存在丰富的自然杀伤 (NK) 细胞 与病情较轻的儿童相比，受感染的儿童患有严重的炎症和低氧血症。 NK 细胞是病毒宿主防御的关键先天介质，在促进和预防病毒感染方面具有重要功能。 解决炎症。 NK 细胞分泌细胞因子，将白细胞募集到活动性感染部位，但也 炎症消退的关键效应物，随后清除发炎组织中的活化白细胞以恢复 体内平衡。因此，NK 细胞促炎和促消退功能的平衡对于治疗至关重要。 两者都能确保宿主防御以及炎症的适当解决。炎症的消退是 由专门的促解决调解员（SPM）精心策划的主动过程，调解员源自 必需脂肪酸可抑制急性炎症反应并发出消退信号，部分是通过影响 NK 细胞功能。在该提案正在进行的工作中，我们发现人类 NK 细胞表达四种不同的 SPM 受体，并且 SPM 脂氧素 A4 增强 NK 细胞分辨率功能。我们提出一个 研究患有严重 RSV 细支气管炎的儿童气道和循环 NK 细胞的转化研究项目 了解为什么自然“制动”信号（即 SPM）无法有效控制病毒引起的 炎。我们的中心假设是，气道 NK 细胞的解析功能在严重的情况下存在缺陷。 RSV 感染会导致不受控制的炎症，并且是 SPM 重新编程的目标 促进解决。为了检验这一假设，我们提出了两个具体目标：1）鉴定 NK 细胞分子 与严重 RSV 疾病相关的特征，2) 确定 SPM 对 NK 细胞分辨率的影响 功能。我们将利用来自患有 RSV 相关呼吸衰竭的儿童的人类儿科样本来 解决这些目标。在 Bruce Levy 博士的指导和指导下，Duvall 博士开发了四个- 年度职业发展计划，提供指导研究、技术技能发展和量身定制 为了实现她成为一名独立医师科学家的目标，需要进行教学培训。重要的是，这 该项目将由具有肺研究专业知识的科学咨询委员会监督 炎症、免疫细胞的转录组分析以及 SPM 对炎症消退的影响， 该提案的三个关键领域。因此，本提案将提供科学的培训和职业生涯 发展技能，为杜瓦尔博士成为一名独立的医师科学家奠定基础 解决感染性气道炎症的人体免疫途径。