SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

Junqueira, C.; Crespo, A.; Ranjbar, S.; Ingber, J.; Parry, B.; David, S.; de Lacerda, L. B.; Lewandrowski, M.; Clark, S. A.; Ho, F.; Vora, S.; Leger, V.; Beackes, C.; Margolin, J.; Russell, N.; Gehrke, L.; Das Adhikari, U.; Henderson, L.; Janssen, E.; Kwon, D.; Sander, C.; Abraham, J.; Filbin, M.; Goldberg, M. B.; Wu, H.; Gautam, M.; Bell, S.; Goldfeld, A.; Lieberman, J.

SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis.