Systems Immunogenetics of Emerging Coronavirus Infections in the Collaborative Cross

AbstractSevere and emerging respiratory virus infections are responsible for considerable human morbidity andmortality and threaten global health. Importantly, significant individual to individual variation in immuneresponses after infection regulates disease severity, a process that is heavily influenced by natural hostgenetic variation in Human populations. In this backdrop, new paradigms are needed to achieve the promise ofprecision medicine, early disease diagnosis/prognosis, susceptibility and risk assessment, and personalizedtreatment. To address this theme, our research programs leverage forward genetic screens in the newlydeveloped collaborative cross (CC) mouse resource to map, identify, and elucidate the polygenic immuneinteractions and molecular mechanisms that govern disease severity following highly pathogenic respiratoryvirus infection. Using the SARS-CoV model, natural genetic variation in the CC expands the range andcomposition of respiratory disease phenotypes, corresponding to selective forces that have shaped humanimmunity. Aim 1 seeks to define quantitative trait loci governing immunity to SARS-CoV and related viruses.Aim 2 identifies causal gene candidates within the QTL and seeks to derive mechanistic insights. Finally, Aim 3integrates these findings across different disease models and between mouse models and human patients.Overall, the goal is to identify the mechanism by which polygenetic traits drive differential disease, to predictand then test disease outcomes in genetically distinct lines that contain different admixtures of susceptibilityloci, and to integrate these findings across diverse disease models and species.