FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

• Published in: Nature (London) Vol. 606; no. 7914; pp. 576 - 584
• Main Authors: Junqueira, Caroline, Crespo, Ângela, Ranjbar, Shahin, de Lacerda, Luna B., Lewandrowski, Mercedes, Ingber, Jacob, Parry, Blair, Ravid, Sagi, Clark, Sarah, Schrimpf, Marie Rose, Ho, Felicia, Beakes, Caroline, Margolin, Justin, Russell, Nicole, Kays, Kyle, Boucau, Julie, Das Adhikari, Upasana, Vora, Setu M., Leger, Valerie, Gehrke, Lee, Henderson, Lauren A., Janssen, Erin, Kwon, Douglas, Sander, Chris, Abraham, Jonathan, Goldberg, Marcia B., Wu, Hao, Mehta, Gautam, Bell, Steven, Goldfeld, Anne E., Filbin, Michael R., Lieberman, Judy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.06.2022; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/31; 13/51; 14; 14/19; 14/34; 14/63; 631/250/1932; 631/250/2499; 631/250/2504/342; 631/326/596/4130; 82/29; Antibodies; Apoptosis; Autopsies; Caspase 1 - metabolism; Caspase-1; Cell death; Chemokines; Coronaviruses; COVID-19; COVID-19 - virology; Cytokines; Disease; DNA-Binding Proteins; Endothelial cells; Flow cytometry; Humanities and Social Sciences; Humans; Infections; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - metabolism; Inflammation - virology; Macrophages; Membranes; Monocytes; Monocytes - metabolism; Monocytes - virology; Mortality; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein; Opsonization; Pathogenesis; Phosphate-Binding Proteins; Plasma; Pore Forming Cytotoxic Proteins; Proteins; Pyroptosis; Receptors, IgG - metabolism; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04702-4

SARS-CoV-2 can cause acute respiratory distress and death in some patients 1 . Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear 2 . Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators 3 . Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients 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 the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis. Antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.