Mary Wilson
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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Published: 06 April 2022
DOI https://doi.org/10.1038/s41586-022-04702-4
Caroline Junqueira, Ângela Crespo, Shahin Ranjbar, Luna B. de Lacerda,
Mercedes Lewandrowski, Jacob Ingber, Blair Parry, Sagi Ravid, Sarah Clark,
Marie Rose Schrimpf, Felicia Ho, Caroline Beakes, Justin Margolin, Nicole Russell,
Kyle Kays, Julie Boucau, Upasana Das Adhikari, Setu M. Vora, Valerie Leger, Lee Gehrke, Lauren Henderson, Erin Janssen, Douglas Kwon, Chris Sander, Jonathan Abraham,
Marcia B. Goldberg, Hao Wu, Gautam Mehta, Steven Bell, Anne E. Goldfeld, Michael R. Filbin & Judy Lieberman
Abstract
SARS-CoV-2 can cause acute respiratory distress and death in some patients[SUP]1[/SUP]. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood[SUP]2[/SUP]. 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 mediators[SUP]3[/SUP]. 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 Fcγ 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.
https://www.nature.com/articles/s41586-022-04702-4_reference.pdf
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Published: 06 April 2022
DOI https://doi.org/10.1038/s41586-022-04702-4
Caroline Junqueira, Ângela Crespo, Shahin Ranjbar, Luna B. de Lacerda,
Mercedes Lewandrowski, Jacob Ingber, Blair Parry, Sagi Ravid, Sarah Clark,
Marie Rose Schrimpf, Felicia Ho, Caroline Beakes, Justin Margolin, Nicole Russell,
Kyle Kays, Julie Boucau, Upasana Das Adhikari, Setu M. Vora, Valerie Leger, Lee Gehrke, Lauren Henderson, Erin Janssen, Douglas Kwon, Chris Sander, Jonathan Abraham,
Marcia B. Goldberg, Hao Wu, Gautam Mehta, Steven Bell, Anne E. Goldfeld, Michael R. Filbin & Judy Lieberman
Abstract
SARS-CoV-2 can cause acute respiratory distress and death in some patients[SUP]1[/SUP]. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood[SUP]2[/SUP]. 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 mediators[SUP]3[/SUP]. 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 Fcγ 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.
https://www.nature.com/articles/s41586-022-04702-4_reference.pdf
