Abstract: Respiratory viruses, such as influenza A virus (IAV) cause high levels of morbidity and mortality in human 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 and quality of an individual's antiviral immune response has important implications for human health, since these genes/pathways could be therapeutically targeted to control viral replication, to treat aberrant immune responses, or they may represent targets for enhancing the safety and efficacy of vaccines against a wide range of viral pathogens. Polymorphic host genes and regulatory networks have a major impact on immune response variation in human populations. However, confounding environmental factors and/or ethical concerns limit the types of studies that can be conducted in humans. Therefore, genetically tractable model systems that capture the range of genetic and phenotypic diversity seen in humans are needed to mechanistically dissect the genetics of immune variation. To address this need, we have used the Collaborative Cross (CC), a highly diverse mouse genetic reference 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-induced innate and adaptive immune responses and disease over a 45 day time-course (Days 2, 4, 7, 10, 15, 28, and 45 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 other complementary Systems Genetics tools, such as the Diversity Outbred (DO) population and CRISPR-mediated genome editing, data sets comparing the host response to other pathogens that are being studied in the context of this U19, and the analysis of gene expression changes and genetic variations in IAV infected human patients, gives us the opportunity to: 1) identify polymorphic genes associated with IAV immune response variation, 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, and 3) test the impact of these genes in the context of human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans.