SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release
Open accessAbstract
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. One sentence summary: Antibody-mediated SARS-CoV-2 infection of monocytes activates inflammation and cytokine release.
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In ageing patients, SARS-CoV-2 can enhance NLRP3 inflammasome activation, IL-1β and IL-18 levels, pyroptosis and DAMP release, further increasing inflammation and COVID-19 pathogenesis.
“In ageing patients, SARS-CoV-2 can potentiate NLRP3 inflammasome activation and IL-1β and IL-18 levels, pyroptosis, and the release of DAMPs (including ATP), further heightening inflammation and COVID-19 pathogenesis74,75.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [74]
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The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19
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Innate and adaptive immunity to SARS-CoV-2 and predisposing factors
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Korean Red Ginseng, a regulator of NLRP3 inflammasome, in the COVID-19 pandemic
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Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes
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Severe COVID ‐19 patients show a dysregulation of the NLRP3 inflammasome in circulating neutrophils
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Pyroptosis-triggered pathogenesis: New insights on antiphospholipid syndrome
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Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease
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Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2
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- Authors
- Junqueira, C., Crespo, Â., Ranjbar, S., Ingber, J., Parry, B., Ravid, S., Lacerda, L. B. D., Lewandrowski, M., Clark, S., Ho, F., Vora, S. M., Leger, V., Beakes, C., Margolin, J., Russell, N., Gehrke, L., Adhikari, U. D., Henderson, L., Janssen, E., Kwon, D., Sander, C., Abraham, J., Filbin, M., Goldberg, M. B., Wu, H., Mehta, G., Bell, S., Goldfeld, A. E., & Lieberman, J.
- Affiliations
- Boston Children's Hospital (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Foundation for Liver Research (GB)
- University of Cambridge (GB)
- Corresponding author
- Junqueira, Caroline
- Lieberman, Judy
- ORCID
- Junqueira, Caroline
- Crespo, Ângela
- Ingber, Jacob
- Parry, Blair
- Ravid, Sagi
- Lewandrowski, Mercedes
- Ho, Felicia
- Vora, Setu M.
- Beakes, Caroline
- Margolin, Justin
- Russell, Nicole
- Gehrke, Lee
- Adhikari, Upasana Das
- Henderson, Lauren
- Janssen, Erin
- Kwon, Douglas
- Sander, Chris
- Abraham, Jonathan
- Filbin, Michael
- Goldberg, Marcia B.
- Wu, Hao
- Mehta, Gautam
- Bell, Steven
- Lieberman, Judy
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2021-03-08
- PMC
- PMC7987031
- OpenAlex
- W3134550228
- Cited by
- 70
- References
- 66
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 11 · 2022: 30 · 2021: 14
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Fast Grants
- British Heart Foundation (RG/16/4/32218)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health (COVID-19)
- National Institute of Allergy and Infectious Diseases (U19AI131135, R01AI124491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- SARS-CoV-2, COVID-19 pandemic, monocytes, NLRP3 inflammasome, AIM2 inflammasome, pyroptosis, caspase-1, gasdermin D, IL-1 family cytokines, severe COVID-19, expression quantitative trait loci, inflammation
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