Systems Immunology profiling of respiratory viral infections in vulnerable populations

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PROJECT SUMMARY/ABSTRACT – PROJECT 2 Acute respiratory viral infections (ARVI) are the most frequently occurring global illness producing significant morbidity and mortality, particularly in vulnerable populations. 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 project is to understand the molecular and cellular immune signatures of the RA response to ARVI to determine how this affects infection severity and autoimmune disease progression. The project includes a detailed systems immunology assessment of acute and long-term airway and adaptive systemic immune responses to naturally occurring ARVI. Project 2 will examine these responses in patients with early RA and established RA on immunosuppression and compare these responses to matched healthy controls. This project is synergistic with the overall program by utilizing similar sample types, timing of sample collection, and common clinical endpoints but differs by studying a distinct host. The individual projects benefit from the overall program's shared multi-omics approaches through a Genomics Core for the samples 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. The first aim is to determine differences in respiratory innate immune profiles in pre/early RA, established RA, and healthy controls in response to ARVI using a multi-omics approach. The second aim will determine if there are differences in adaptive cellular responses including a detailed characterization of viral-specific and autoantigen specific populations. The third aim will utilize TotalSeq (scRNA-seq, TCR/BCR sequencing and surface protein quantification), to determine the relationship between mucosal and systemic responses. This study will determine both how mucosal inflammation contributes to autoimmune pathogenesis and the host response to ARVI. It will produce novel mechanistic insights into the diversity and commonality of adult and RA immune response to acute respiratory viruses and use cutting-edge methods to provide mechanistic insights.