Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross

Abstract: Emerging viruses, such as SARS-CoV, influenza A virus (IAV), and West Nile virus (WNV) causehigh levels of morbidity and mortality in Human populations. Host immune responses can play either protectiveor a pathologic role during viral infections. Therefore, understanding of the regulatory networks and signalingpathways that determine the magnitude and quality of an individual's antiviral immune response has importantimplications for human health, since these genes/pathways could be therapeutically targeted to treat virus-induced disease, or 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, such as the Collaborative Cross (CC) are needed tomechanistically dissect the genetics of immune variation. Our research team has quantified variation inbaseline, as well as SARS-CoV, IAV, and WNV-induced immune responses in a panel of 110 CC RIX lines(reproducible F1 crosses between CC recombinant inbred (RI) lines that model heterozygous humanpopulations). To our knowledge, this represents to most comprehensive analysis of immune response variationever conducted in a genetic reference population, and in ongoing QTL mapping studies, we have identified100+ quantitative trait loci (QTL) associated with variation in virus-induced innate and adaptive immunity,inflammation and disease. Our program, which includes expertise in viral pathogenesis, innate and adaptiveimmunity, and quantitative genetics will use this unprecedented data base to: 1) identify and characterizepolymorphic host genes that drive variation in virus-induced disease, 2) test how interactions between differentpolymorphic genes/loci shape the host immune response, 3) test how these genes impact responses to otherviral pathogens, or function during allergy/auto-immunity, and 4) test the impact of these genes in the contextof human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans.These studies will significantly enhance our understanding of how host genetic variation shapes virus-inducedimmunity and/or disease.