Systems Immunology profiling of respiratory viral infections in vulnerable populations

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SUMMARY/ABSTRACT – OVERALL 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 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. Similarly, adults with chronic inflammatory diseases or on immunosuppression suffer significant consequences from ARVI. Adults with rheumatoid arthritis (RA) have an increased risk for infection and respiratory mucosal inflammation may contribute to autoimmune disease severity. The goal of this research program is to understand the molecular and cellular immune signatures of the vulnerable host response to ARVI to identify novel therapies and individuals at risk for clinical complications. The program includes a detailed systems immunology assessment of acute and long-term airway and adaptive systemic immune responses to naturally occurring ARVI. The first project will identify how asthma, atopy, and obesity lead to maladaptive immune responses to ARVI in pediatric subjects. The second project will examine host response to ARVI in adults with RA. RA is a disease provoked by environmental stimuli like respiratory infections and RA patients have baseline immune differences. These projects are complementary and synergistic by utilizing similar sample types and timing of sample collection, and common clinical endpoints. The individual projects benefit from shared multi-omics approaches through a Genomics Core for the sample processing and generation of airway host transcriptome, proteome, epithelial methylation, and viral quantity and expression data, along with host genetics. There is also a shared 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. This will allow for direct comparisons to be made between the adult and pediatric cohorts to identify common and divergent responses to ARVI. In the Overall, the first Specific Aim is to determine similar and divergent host responses to ARVI considering the pediatric allergy/asthma (Project 1) and adult RA (Project 2) cohorts. The second Specific Aim is to consider these host responses in the context of other large publicly-funded studies of viral infection through meta-analyses. The final Specific Aim will be to develop predictive spatiotemporal models of how mucosal and systemic immune responses to ARVI influence clinical outcomes. Our research program will produce novel mechanistic insights into the diversity and commonality of human immune responses to acute respiratory viruses and use cutting- edge methods to identify potential therapies.