Systems Immunogenetics of Influenza Virus Infection in the Collaborative Cross

Abstract: Respiratory viruses, such as influenza A virus (IAV) cause high levels of morbidity and mortality inHuman populations. Host immune responses can play either protective or a pathologic role during infection.Therefore, understanding of the regulatory networks and signaling pathways that determine the magnitude andquality of an individual's antiviral immune response has important implications for human health, since thesegenes/pathways could be therapeutically targeted to control viral replication, to treat aberrant immuneresponses, or they may represent targets for enhancing the safety and efficacy of vaccines against a widerange of viral pathogens.Polymorphic host genes and regulatory networks have a major impact on immune response variation in humanpopulations. However, confounding environmental factors and/or ethical concerns limit the types of studiesthat can be conducted in humans. Therefore, genetically tractable model systems that capture the range ofgenetic and phenotypic diversity seen in humans are needed to mechanistically dissect the genetics of immunevariation. To address this need, we have used the Collaborative Cross (CC), a highly diverse mouse geneticreference population, to identify and characterize polymorphic host genes that regulate baseline and IAV-induced innate and adaptive immunity. As part of this effort, we have quantified variation in virus-inducedinnate and adaptive immune responses and disease over a 45 day time-course (Days 2, 4, 7, 10, 15, 28, and45 post infection) in a panel of 110 CC RIX lines (reproducible F1 crosses between CC recombinant inbred(RI) lines that model heterozygous Human populations). This resource, when combined with othercomplementary Systems Genetics tools, such as the Diversity Outbred (DO) population and CRISPR-mediatedgenome editing, data sets comparing the host response to other pathogens that are being studied in thecontext of this U19, and the analysis of gene expression changes and genetic variations in IAV infected humanpatients, gives us the opportunity to: 1) identify polymorphic genes associated with IAV immune responsevariation, and test their impact on other aspects of the antiviral response or virus-induced disease process, 2)test how these genes impact responses to other viral pathogens, or function during allergy/auto-immunity, and3) test the impact of these genes in the context of human infections to identify targets for diagnosis, preventionand therapeutic interventions in humans.