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

项目摘要 呼吸道合胞病毒(RSV)是引起毛细支气管炎的主要原因，也是引起毛细支气管炎的主要原因 用于婴儿住院治疗。感染RSV的儿童中的一部分会发展成压倒性的炎症，导致 导致呼吸衰竭甚至死亡，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。我们发现自然杀伤(NK)细胞在呼吸道合胞病毒的呼吸道中含量丰富。 与病情不太严重的儿童相比，感染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质，在促进和促进病毒宿主防御中具有重要作用。 消炎解毒。NK细胞分泌细胞因子，将白细胞招募到活跃的感染部位，但也 炎症消退的关键效应因子，用于稍后清除炎症组织中激活的白细胞以恢复 动态平衡。因此，NK细胞的促炎和促分解功能之间的平衡对于 两者都确保了宿主的防御以及炎症的适当消退。炎症的消退是 由专门的亲解析调解器(SPM)协调的活动过程，调解器派生自 抑制急性炎症反应和消退信号的必需脂肪酸，部分通过影响 NK细胞功能。在为这项提案进行的工作中，我们发现人类NK细胞表达四种不同的 SPM的受体和SPM的脂氧素A4增强NK细胞的分解功能。我们提出了一个 研究重症呼吸道合胞病毒毛细支气管炎患儿呼吸道和循环NK细胞的翻译研究项目 理解为什么自然的“刹车”信号(即SPM)在控制病毒诱导方面无效 发炎。我们的中心假设是重症患者的呼吸道NK细胞的分解功能存在缺陷。 RSV感染导致不受抑制的炎症，是SPM重新编程的目标 推动解决问题。为了验证这一假设，我们提出了两个具体的目标：1)鉴定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。我们将利用患有RSV相关性呼吸衰竭的儿童的人类儿科样本来 实现这些目标。在布鲁斯·利维博士的指导和指导下，杜瓦尔博士开发出了四种- 年提供职业发展计划辅导研究、技术技能发展，并量身定做 为了实现成为一名独立的内科科学家的目标，她需要接受说教培训。重要的是，这 该项目将由一个在肺脏研究方面具有专业知识的科学咨询委员会监督 炎症，免疫细胞的转录分析，以及SPM对炎症消退的影响， 这项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专注于独立内科医生和科学家的人奠定基础 在人类免疫途径上化解感染性呼吸道炎症。

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.