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

基本信息

批准号：
10460167
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460167
关键词：
Active Sites Acute Address Adopted Adrenal Cortex Hormones Advisory Committees 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

项目摘要

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.

项目摘要呼吸综合病毒（RSV）是小儿患者细支气管炎的主要原因，是主要原因用于婴儿住院。 RSV感染儿童的一部分会出现压倒性的炎症，导致呼吸衰竭甚至死亡，但这种严重的RSV疾病表型的免疫生物学不完全理解。我们发现自然杀手（NK）细胞在RSV-的气道中丰富感染的儿童相对于患有严重疾病的患者感染了深远的感染和低氧血症。 NK细胞是病毒宿主防御的关键先天介体，在促进和解决炎症。 NK细胞秘密细胞因子募集白细胞到活性感染部位，但也是炎症分辨率的关键作用，以后清除发炎组织的活化的白细胞以恢复稳态。这就是NK细胞的促炎和促促分解特征的平衡是至关重要的两者都确保宿主防御以及适当的感染分辨率。感染的分辨率为由专门的支持解析调解人（SPM）策划的主动过程，来自限制急性炎症反应和解析信号的必需脂肪酸，部分通过影响 NK细胞功能。在为该提案进行的工作中，我们发现人NK细胞表达了四个不同的 SPM的受体和SPM Lipoxin A4增强了NK细胞分辨率的功能。我们提出了一个转化研究项目，研究严重RSV细支气管炎儿童的气道和循环NK细胞要了解为什么自然的“制动”信号（即SPM）无效控制病毒诱导炎。我们的中心假设是气道NK细胞的分辨率功能在重度中有缺陷 RSV感染有助于无限制注射，是SPMS重编程的靶标促进解决方案。为了检验该假设，我们提出了两个具体目的：1）识别NK细胞分子与严重的RSV疾病相关的签名和2）确定SPM对NK细胞分辨率的影响功能。我们将利用与RSV相关呼吸道失效儿童的人类儿科样本解决这些目标。在布鲁斯·利维（Bruce Levy）博士的指导和心态下，杜瓦尔（Duvall）博士开发了四个一年的职业发展计划，提供指导的研究，技术技能发展和量身定制的教义训练需要实现成为独立的身体科学家的目标。重要的是，这个项目将由科学咨询委员会监督，该委员会在研究肺部研究方面具有专业知识炎症，免疫细胞的转录组分析以及SPM对炎症分辨率的影响，该提案的三个关键领域。因此，该建议将提供科学培训和职业发展技巧，为杜瓦尔博士成为以独立的身体科学家为基础的基础在解决感染性气道炎症的人类免疫病道上。