SARS-CoV-2 is causing an unprecedented pandemic that is likely to result in millions of deaths, with devastating economic and public health consequences. Approximately 10% of SARS-CoV-2 infections result in COVID-19 pneumonia that progresses to acute respiratory distress syndrome (ARDS). A growing body of evidence suggests that the host inflammatory response plays a major role in driving severe disease outcomes. Therefore, it is essential to understand how SARS-CoV-2 interacts with the host inflammatory response to drive COVID-19 pathogenesis. Recent studies suggest that bats, which are the natural reservoir of group 2b coronaviruses like SARS-CoV-2, have dampened NLRP3 function, which may allow these viruses to infect bats without causing serious disease. This indicates that NLRP3 or other NLR inflammasomes, may play an important role in SARS-CoV-2-induced inflammation and thereby drive virus-induced respiratory pathology. Given that these genes and pathways are also polymorphic in humans, this raises the possibility that genetic variation in NLR gene networks may contribute to variation in SARS-CoV-2 susceptibility. Therefore, we propose to take advantage of our research team’s unique capabilities in SARS-CoV-2 pathogenesis and mouse genetics to directly test whether NLRP3 or other NLR inflammasome pathways contribute to SARS-CoV2-induced disease. We will also test whether genetic variation in these pathways affects disease outcome or virus-induced immunity. This effort will be further enhanced by a collaboration with Drs. Gary Nolan and Richard Ulevitch (U19AI100627), which will allow us to test whether these genes/pathways are activated during SARS-CoV-2 infection in humans. Therefore, the proposed studies, which fall within the scope or the parent grant U19AI100625, achieve three critical research goals by: 1) testing the role of NLRP3 and related pathways in driving SARS-CoV-2 disease pathogenesis, 2) testing whether genetic variation in these pathways affects SARS-CoV-2-induced inflammatory responses or adaptive immunity, and 3) developing novel mouse models that reproduce key features of COVID-19 disease pathogenesis and inflammation.