PROJECT SUMMARY/ABSTRACT – PROJECT 1 Acute respiratory viral infections (ARVI) are the most frequently occurring global illness producing significant morbidity and mortality, particularly in vulnerable populations. Children suffer higher frequencies of ARVI than adults and often experience re-infections. Common chronic diseases of childhood, most notably asthma but also allergies (atopy) and obesity, can predispose to increased severity of ARVI. The goal of Project 1 is to understand the longitudinal airway and systemic, innate and adaptive, immune responses to ARVI in vulnerable groups of children with asthma, atopy, and obesity compared to control children without these comorbidities. Furthermore, we will link these responses to clinical outcomes including infection duration and severity. Project 1 is highly synergistic with Project 2 and the Overall program by utilizing similar sample types, timing of sample collection, and common clinical endpoints; it differs by studying a distinct population of at-risk children and it includes disease specific assessments of allergic immune responses. Project 1 benefits from the overall program’s shared multi-omics approaches through a Genomics Core for the sample processing and generation of airway host transcriptome, proteome, DNA methylation, and viral quantity and expression data, along with host genetics. Similarly, it shares the Adaptive Phenotyping Core for the generation of high dimensional cytometry data to broadly characterize immune cell phenotypes and for detailed identification of antigen-specific cells. The first aim will determine differences in longitudinal respiratory innate immune profiles in children with and without asthma, atopy, and obesity in response to ARVI using multi-omic assessments of airway samples. The second aim will determine differences in short-term and long-term adaptive cellular responses including a detailed characterization of viral-specific and allergen-specific T cell populations. The third aim will utilize single cell gene expression, TCR/BCR sequencing, and surface protein quantification (TotalSeq) to provide cell specific granularity of both mucosal and systemic responses. This study will determine networks of airway and systemic immune pathways that lead to adaptive and maladaptive responses to ARVI in vulnerable children. Our research program will produce novel mechanistic insights into the diversity and commonality of immune responses to ARVI and use cutting-edge methods to provide novel insights for future studies of disease prevention and treatment.