Multidimensional analysis of the regulatory T cell response in children with severe viral pneumonia - Abstract Respiratory viruses are ubiquitous pathogens that cause a spectrum of clinical diseases ranging from asymptomatic carriage to severe pneumonia. Healthy children are much more likely to develop severe viral pneumonia than healthy adults and lung injury during childhood is associated with long-term impairments in respiratory health. There is a paucity of information regarding why children are highly susceptible to viral pneumonia and how they recover from severe disease. Children with severe viral pneumonia present to the pediatric intensive care unit with an established infection and lung injury. Currently, therapies for viral-induced lung injury are supportive and do not directly modify the pathology or accelerate recovery. Thus, there is a need to understand the age-specific mechanisms that promote recovery from severe viral pneumonia in children to aid in developing novel therapeutic strategies. Infection of mice with murine-adapted strains of influenza A virus (IAV) mimics many of the clinical features of severe viral pneumonia. Our group developed a mouse model of IAV infection that recapitulates clinical disease in children less than 5 years of age. We previously reported that juvenile mice exhibit a persistent, excessive inflammatory response to IAV despite adequate viral clearance. The resulting lung injury suggests juveniles fail to resolve inflammation and fail to repair the alveolar epithelium during severe disease. Regulatory T (Treg) cells mediate inflammation resolution and tissue repair. Adult murine models define an essential role for Treg cells in the recovery from severe viral pneumonia, however, studies in age-appropriate murine models are lacking. This proposal hypothesizes that during severe viral pneumonia in children, the reparative function of Treg cells is impaired, and Treg cells fail to mitigate excessive proinflammatory responses and promote tissue repair. The specific aims are 1) Determine whether juvenile regulatory T cells have impaired reparative functions during severe viral pneumonia, 2) Determine whether the age-specific lung microenvironment during severe influenza pneumonia affects regulatory T cell pro-recovery functions, and 3) Determine if alveolar regulatory T cell transcriptional signatures are associated with outcomes in pediatric patients with severe viral pneumonia.The project was explicitly designed to facilitate the career development of the primary investigator (PI). It will provide experiential learning augmented with structured training opportunities to advance the PI to independent investigator status. Specific training domains include advanced methods of assessing alveolar injury and repair, flow cytometric analysis of immune cell phenotypes, assays to assess T cell function, systems biology approaches to identifying novel genomic determinates of T cell function, and design of translational studies using patients’ clinical and molecular data. This proposal will lay the foundation for an iterative translational approach the PI can continue to use throughout his career to achieve his long-term goal of identifying therapeutic targets to hasten recovery and improve long-term respiratory health of children with severe viral pneumonia.
