Generating Novel Humanized Mouse Models for in vivo COVID19 Mechanism Studies and Therapeutics Tests

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PROJECT SUMMARY The COVID19 pandemic has spread across the globe with unprecedented speed and devastation. With infected individuals rising past 1.4 million in the US, there is a dizzying amount of information causing confusion around which tissues SARS-CoV-2 infects and how it triggers catastrophic immune response and tissue destruction. Furthermore, with the rapidly increasing number of candidate therapies, there is an urgent need for animal models that faithfully recapitulate the human disease and is scalable to provide power for preclinical testing. We will use our extensive expertise in mouse genetics to generate two novel mouse models that express human viral receptor ACE2 (hACE2) in either selected cell types/tissues of interest or in the endogenous pattern of ACE2 expression in mice. Expression of the hACE2 gene will allow efficient SARS-CoV-2 infection. We will use infected humanized mice to dissect the progression of COVID19 from initial infection of host cells, to antiviral and pro-inflammatory responses, to development of acute respiratory distress syndrome, using single cell approaches such as single cell RNAseq. In parallel, we will also use infected humanized mice to test the effectiveness of candidate FDA approved drugs for their effectiveness in halting COVID19. We expect that these humanized mouse models will be valuable platforms for a large number of COVID research directions listed as Areas of High Priority in PAR-20-177.