Identifying Genetic Regulators and New Models of Wild Type Coronavirus Pathogenesis

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