TY - JOUR N2 - SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fc? receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis. SN - 0028-0836 SP - 576 AV - public UR - https://doi.org/10.1038/s41586-022-04702-4 ID - discovery10149998 N1 - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions. JF - Nature PB - NATURE PORTFOLIO KW - Antimicrobial responses KW - Immune cell death KW - Monocytes and macrophages KW - SARS-CoV-2 A1 - Junqueira, Caroline A1 - Crespo, Ângela A1 - Ranjbar, Shahin A1 - De Lacerda, Luna B A1 - Lewandrowski, Mercedes A1 - Ingber, Jacob A1 - Parry, Blair A1 - Ravid, Sagi A1 - Clark, Sarah A1 - Schrimpf, Marie Rose A1 - Ho, Felicia A1 - Beakes, Caroline A1 - Margolin, Justin A1 - Russell, Nicole A1 - Kays, Kyle A1 - Boucau, Julie A1 - Das Adhikari, Upasana A1 - Vora, Setu M A1 - Leger, Valerie A1 - Gehrke, Lee A1 - Henderson, Lauren A1 - Janssen, Erin A1 - Kwon, Douglas A1 - Sander, Chris A1 - Abraham, Jonathan A1 - Goldberg, Marcia B A1 - Wu, Hao A1 - Mehta, Gautam A1 - Bell, Steven A1 - Goldfeld, Anne E A1 - Filbin, Michael R A1 - Lieberman, Judy EP - 584 Y1 - 2022/06/16/ TI - Fc?R-mediated SARS-CoV-2 infection of monocytes activates inflammation VL - 606 ER -