PROJECT SUMMARY In response to “NOT-RM-20-015”, we propose an urgent competitive revision to The Jackson Laboratory Knockout Mouse Phenotyping Project (KOMP2) to develop the next generation of precision mouse models for mechanistic discovery of SARS-CoV2 infection and therapeutic discovery of COVID-19 disease treatments. The worldwide response to the COVID-19 pandemic has triggered a surge in demand for animal models to understand the underlying biology and pathology of SARS-CoV-2 infection and for the preclinical development of novel therapeutic strategies. Several mouse models have recently been reported that respond with varying degrees to SARS-CoV-2 infection. However, given the diversity of patient outcomes, any one mouse model on a standard inbred genetic background does not reflect the impact of host genetic context on SARS-CoV-2 infection and response to treatment. We therefore propose to create a second-generation mouse model platform incorporating diverse genetic backgrounds, to characterize the variation in SARS-CoV-2 infection dynamics and the development of clinically-relevant disease. The proposed project will rapidly provide the research community with an urgently needed resource for linking the variability in COVID-19 disease outcome with underlying host genetic features, and for developing precision therapies tailored to treat the individual patient. Our Specific Aims are: 1) To create a panel of genetically diverse transgenic models for SARS-CoV-2 infection; 2) To characterize infectivity, phenotypic response, disease outcome, and transcriptome heterogeneity of these models; and 3) To distribute these models and our outcome data to the scientific community.

RELEVANCE TO PUBLIC HEALTH The Knockout Mouse Phenotyping Program (KOMP2) seeks to create an encyclopedia of gene function for the ~20,000 genes in the mouse and to ultimately create a resource for understanding gene function in humans. The Jackson Laboratory (JAX) will contribute to this goal by efficiently generating knockout lines and sharing functional data for 1,500 mouse genes. The JAX team will enhance the value of these data by linking them with current genetic and biological knowledge, enabling the scientific community to discover the roles of these genes in human health and disease.