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

项目摘要 呼吸道合胞病毒（RSV）是小儿毛细支气管炎的主要病因， 用于婴儿住院治疗。一部分RSV感染的儿童会出现严重的炎症， 呼吸衰竭甚至死亡，但这种严重的RSV疾病表型背后的免疫生物学 是不完全理解的。我们已经发现自然杀伤（NK）细胞在RSV的气道中是丰富的- 与病情不太严重的儿童相比，感染严重的儿童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体，并且在促进和抑制病毒宿主防御中具有重要功能。 消除炎症。NK细胞分泌细胞因子以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，以随后从发炎组织中清除活化的白细胞， 体内平衡因此，NK细胞的促炎性和促消退特征的平衡对于 两者都确保宿主防御以及炎症的适当解决。炎症消退是 一个由专门的促消退介质（SPM）协调的主动过程， 必需脂肪酸，抑制急性炎症反应和信号的解决，部分是通过影响 NK细胞功能。在这项提案的进展中，我们发现人类NK细胞表达四种不同的基因， 受体的SPM和SPM脂氧素A4增强NK细胞的分辨率功能。我们提出了一个 研究重度RSV细支气管炎患儿气道和循环NK细胞的转化研究项目 为了理解为什么自然的“制动”信号（即SPM）在控制病毒诱导的 炎症我们的中心假设是气道NK细胞的分辨功能在重度哮喘中是有缺陷的。 RSV感染导致不受限制的炎症，并且是SPM重编程的靶点， 促进决议。为了验证这一假设，我们提出了两个具体的目标：1）确定NK细胞分子 与严重RSV疾病相关的特征和2）确定SPM对NK细胞分辨率的影响 功能我们将利用来自RSV相关呼吸衰竭儿童的人类儿科样本， 实现这些目标。在布鲁斯·利维博士的指导和指导下，杜瓦尔博士制定了一个四- 一年的职业发展计划，以提供指导研究，技术技能发展，并量身定制 为了实现她成为一名独立的物理学家和科学家的目标，她需要进行教学训练。重要的是这 该项目将由一个具有肺疾病研究专业知识的科学咨询委员会监督。 炎症，免疫细胞的转录组学分析，以及SPM对炎症消退的影响， 这是该提案的三个关键领域。因此，这项建议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学科学家奠定基础。 解决感染性气道炎症的人体免疫途径。

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.