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.
Respiratory syncytial virus (RSV) bronchiolitis is a prevalent pediatric disease that can lead to substantial inflammation, respiratory failure, and death. Natural killer (NK) cells are important mediators of anti-viral host defense and are targets for specialized pro-resolving mediators (SPMs) that signal to restrain and resolve inflammation in health. We propose to determine the pro-resolving effects of SPMs on NK cells from children with severe RSV bronchiolitis, with the ultimate goal of developing novel therapies that accelerate inflammation resolution.
