Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 529

The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.

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

Published version of a preprint

Open this paper in CoChat — free account

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41586-022-04802-1

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 25 references

Research works printed but not linked: 55

  1. Acharya, D., Liu, G. & Gack, M. U. Dysregulation of type I interferon responses in COVID-19. Nat. Rev. Immunol. 20, 397–398 (2020). · DOI · Paper page
  2. Pairo-Castineira, E. et al. Genetic mechanisms of critical illness in COVID-19. Nature 591, 92–98 (2020). · DOI · Paper page
  3. Nienhold, R. et al. Two distinct immunopathological profiles in autopsy lungs of COVID-19. Nat. Commun. 11, 5086 (2020). · DOI · Paper page
  4. Zhou, Z. et al. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe 27, 883–890 (2020). · DOI · Paper page
  5. Dolan, M. E. et al. Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease. Sci. Rep. 10, 20848 (2020). · DOI
  6. Delorey, T. M. et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 595, 107–113 (2021). · DOI · Paper page
  7. Singanayagam, A. et al. Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020. Euro Surveill. 25, 2001483 (2020). · DOI · Paper page
  8. Decker, A. et al. Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation. Am. J. Transplant. 20, 3239–3245 (2020). · DOI
  9. Jeong, H. W. et al. Viable SARS-CoV-2 in various specimens from COVID-19 patients. Clin. Microbiol. Infect. 26, 1520–1524 (2020). · DOI
  10. Liu, W. D. et al. Prolonged virus shedding even after seroconversion in a patient with COVID-19. J. Infect. 81, 318–356 (2020).
  11. Folgueira, M. D., Luczkowiak, J., Lasala, F., Perez-Rivilla, A. & Delgado, R. Prolonged SARS-CoV-2 cell culture replication in respiratory samples from patients with severe COVID-19. Clin. Microbiol. Infect. 27, 886–891 (2021). · DOI
  12. Lucas, C. et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 584, 463–469 (2020). · DOI · Paper page
  13. Wu, C. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 180, 934–943 (2020). · DOI · Paper page
  14. Rodrigues, T. S. et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J. Exp. Med. 218, e20201707 (2021). · DOI · Paper page
  15. Henry, B. M. et al. Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: a pooled analysis. Am. J. Emerg. Med. 38, 1722–1726 (2020). · DOI · Paper page
  16. Sefik, E. et al. A humanized mouse model of chronic COVID-19. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-01155-4 (2021). · DOI
  17. Grant, R. A. et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 590, 635–641 (2021). · DOI · Paper page
  18. Pruijssers, A. J. et al. Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice. Cell Rep. 32, 107940 (2020). · DOI · Paper page
  19. Havervall, S. et al. Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers. JAMA 325, 2015–2016 (2021). · DOI · Paper page
  20. Nasserie, T., Hittle, M. & Goodman, S. N. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw. Open 4, e2111417 (2021). · DOI · Paper page
  21. Ginestra, J. C., Mitchell, O. J. L., Anesi, G. L. & Christie, J. D. COVID-19 critical illness: a data-driven review. Annu. Rev. Med. 73, 95–111 (2022). · DOI
  22. Phetsouphanh, C. et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat. Immunol. 23, 210–216 (2022). · DOI · Paper page
  23. Basile, K. et al. Cell-based culture of SARS-CoV-2 informs infectivity and safe de-isolation assessments during COVID-19. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1579 (2020). · DOI
  24. Vora, S. M., Lieberman, J. & Wu, H. Inflammasome activation at the crux of severe COVID-19. Nat. Rev. Immunol. 21, 694–703 (2021). · DOI · Paper page
  25. Major, J. et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science 369, 712–717 (2020). · DOI · Paper page
  26. Polak, S. B., Van Gool, I. C., Cohen, D., von der Thusen, J. H. & van Paassen, J. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod. Pathol. 33, 2128–2138 (2020). · DOI · Paper page
  27. Tian, S. et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod. Pathol. 33, 1007–1014 (2020). · DOI · Paper page
  28. Menter, T. et al. Postmortem examination of COVID‐19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 77, 198–209 (2020). · DOI · Paper page
  29. Barton, L. M., Duval, E. J., Stroberg, E., Ghosh, S. & Mukhopadhyay, S. Covid-19 autopsies, Oklahoma, USA. Am. J. Clin. Pathol. 153, 725–733 (2020). · DOI · Paper page
  30. Strunz, M. et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 11, 3559 (2020). · DOI · Paper page
  31. Choi, J. et al. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell 27, 366–382 e367 (2020). · DOI · Paper page
  32. Hassan, A. et al. A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell. 182, 744–753 (2020). · DOI · Paper page
  33. Muus, C. et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 27, 546–559 (2021). · DOI · Paper page
  34. Bournazos, S., Gupta, A. & Ravetch, J. V. The role of IgG Fc receptors in antibody-dependent enhancement. Nat. Rev. Immunol. 20, 633–643 (2020). · DOI · Paper page
  35. Bournazos, S. & Ravetch, J. V. Fcγ receptor function and the design of vaccination strategies. Immunity 47, 224–233 (2017). · DOI
  36. Hoepel, W. et al. High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages. Sci. Transl. Med. 13, eabf8654 (2021). · DOI · Paper page
  37. Evren, E. et al. Distinct developmental pathways from blood monocytes generate human lung macrophage diversity. Immunity 54, 259–275 (2021). · DOI
  38. Chua, R. L. et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020). · DOI · Paper page
  39. Zhang, J. Y. et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat. Immunol. 21, 1107–1118 (2020). · DOI · Paper page
  40. Allen, I. C. et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30, 556–565 (2009). · DOI · Paper page
  41. Thomas, P. G. et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30, 566–575 (2009). · DOI · Paper page
  42. Pothlichet, J. et al. Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells. PLoS Pathog. 9, e1003256 (2013). · DOI
  43. Ferreira, A. C. et al. SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes. Cell Death Discov. 7, 43 (2021). · DOI · Paper page
  44. Pan, P. et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat. Commun. 12, 4664 (2021). · DOI · Paper page
  45. Xu, H. et al. SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway. Virology 568, 13–22 (2022). · DOI
  46. Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019). · DOI · Paper page
  47. Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 25, 2000045 (2020).
  48. Schäfer, A. et al. Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo. J. Exp. Med. 218, e20201993 (2020). · DOI
  49. Yu, H. et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129, 959–969 (2017). · DOI
  50. Israelow, B. et al. Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling. J. Exp. Med. 217, e20201241 (2020). · DOI · Paper page
  51. Perera, A. P. et al. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci. Rep. 8, 8618 (2018). · DOI · Paper page
  52. Dixon, K. O. et al. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 595, 101–106 (2021). · DOI · Paper page
  53. Wei, J. et al. Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. Cell 184, 76–91 (2020). · DOI · Paper page
  54. Sun, F., Xiao, G. & Qu, Z. Murine bronchoalveolar lavage. Bio Protoc. 7, e2287 (2017).
  55. Stack, J. H. et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J. Immunol. 175, 2630–2634 (2005). · DOI

Cited by

See all 529

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Inflammasome activation in infected macrophages drives COVID-19 pathology. https://app.cochat.ai/papers/10.1038/s41586-022-04802-1
The paper
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., . . . Flavell, R. A. (2022). Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature. https://doi.org/10.1038/s41586-022-04802-1

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.