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

PROJECT SUMMARY The COVID19 pandemic has spread across the globe with unprecedented speed anddevastation. With infected individuals rising past 1.4 million in the US, there is a dizzyingamount of information causing confusion around which tissues SARS-CoV-2 infects and how ittriggers catastrophic immune response and tissue destruction. Furthermore, with the rapidlyincreasing number of candidate therapies, there is an urgent need for animal models thatfaithfully 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 modelsthat express human viral receptor ACE2 (hACE2) in either selected cell types/tissues of interestor in the endogenous pattern of ACE2 expression in mice. Expression of the hACE2 gene willallow efficient SARS-CoV-2 infection. We will use infected humanized mice to dissect theprogression of COVID19 from initial infection of host cells, to antiviral and pro-inflammatoryresponses, to development of acute respiratory distress syndrome, using single cell approachessuch as single cell RNAseq. In parallel, we will also use infected humanized mice to test theeffectiveness of candidate FDA approved drugs for their effectiveness in halting COVID19. Weexpect that these humanized mouse models will be valuable platforms for a large number ofCOVID research directions listed as Areas of High Priority in PAR-20-177.