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Cited by 529

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Inflammasome activation in infected macrophages drives COVID-19 pathology

Open access
Sefik, Esen, Qu, Rihao, Junqueira, Caroline, Kaffe, Eleanna, Mirza, Haris, Zhao, Jun, Brewer, J. Richard, Han, Ailin, Steach, Holly R., Israelow, Benjamin, Blackburn, Holly N., Velazquez, Sofia E., Chen, Y. Grace, Halene, Stephanie, Iwasaki, Akiko, Meffre, Eric, Nussenzweig, Michel, Lieberman, Judy, Wilen, Craig B., Kluger, Yuval, Flavell, Richard A.·2022·Nature
DOI 10.1038/s41586-022-04802-1

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Abstract

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system1–20. Blocking either viral replication with remdesivir21–23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle. A new humanized mouse model for COVID-19 demonstrates SARS-CoV-2 infection and subsequent activation of inflammasomes in human macrophages as a critical driver of disease.

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Cited by

Metadata

Authors
Sefik, E., Qu, R., Junqueira, C., Kaffe, E., Mirza, H., Zhao, J., Brewer, J. R., Han, A., Steach, H. R., Israelow, B., Blackburn, H. N., Velazquez, S. E., Chen, Y. G., Halene, S., Iwasaki, A., Meffre, E., Nussenzweig, M., Lieberman, J., Wilen, C. B., Kluger, Y., & Flavell, R. A.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-04-28
Volume
606
Issue
7914
Pages
585-593
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04802-1
OpenAlex
W4225159577
Cited by
529
References
25
FWCI
32.94
Type
journal article
Language
en
Open access
bronze
Licence
Funders
  • Howard Hughes Medical Institute (HHMI Investigator)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM135928, R35 GM142687, GM131642)
  • Damon Runyon Cancer Research Foundation (DRG-2316-18)
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (2T32AI007517, R01AI157488, AI118855, K08 AI128043)
  • Rita Allen Foundation
  • Division of Cancer Prevention, National Cancer Institute (U01 CA260507)
  • G. Harold and Leila Y. Mathers Foundation
  • Fast Grant from Emergent Ventures at the Mercatus Center Ludwig Family Foundation
  • U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (CA016359)
  • This work was funded by the Howard Hughes Medical Institute
  • Harvard Lemann Brazil Research Fund
  • Burroughs Wellcome Fund
  • JGW Patterson Foundation

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