Identifying Genetic Regulators and New Models of Wild Type Coronavirus Pathogenesis

ABSTRACTSARS-CoV, and more recently MERS-CoV, are human coronaviruses that have emerged fromzoonotic populations to infect and cause severe disease in humans. Our understanding ofcoronavirus pathogenesis is largely limited to what can be observed in small animal models whichappear to recapitulate the disease seen in humans. The SARS-CoV mouse model relies on amouse adapted strain of virus, MA15, as the wild type human isolates replicate in mice but do notcause appreciable signs of disease. Replication models also fail to capture key aspects of thehuman response to infection - respiratory dysfunction, inflammation and other signs of disease.As such, replication models cannot be used to assess either antiviral therapeutics or vaccineefficacy. While mouse adapted SARS-CoV infection recapitulates many of the aspects of humanSARS-CoV disease, the virus has six point mutations scattered throughout the genome and wasnot generated until years after the end of the SARS epidemic. Passage models run the risk ofaltering virus tropism or replication from what occurs in the natural host and require sequencingand extensive analysis know the location and effect of each mutation. Importantly, coronaviruspassage experiments were recently restricted during the Gain of Function research pause andcould now fall under the HHS P3CO Framework, thus limiting our ability to rapidly identify diseasemodels for emerging pathogens. Additionally, a passage approach to generating a diseasemodels is time consuming, something that cannot be afforded in the context of a novel virusoutbreak. By generating a new mouse model of wild type SARS-CoV pathogenesis we willprovide an important tool for the evaluation of the pathogenic potential of emerging zoonoticcoronaviruses as well as a resource for testing novel therapeutics and vaccines. Additionally wewill identify genetic regulators that dictate a pathogenic response to wild type SARS-CoVinfection.