SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology

J Exp Med. 2020 Dec 7;217(12):e20201129. doi: 10.1084/jem.20201129.


Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adult
  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / physiology*
  • COVID-19
  • Cell Death
  • Coronavirus Infections / blood
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / pathology
  • Coronavirus Infections / virology*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Extracellular Traps / physiology*
  • Female
  • HeLa Cells
  • Humans
  • Male
  • Neutrophil Activation
  • Pandemics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / blood
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology*
  • SARS-CoV-2
  • Serine Proteases / metabolism
  • Suction
  • Trachea / immunology


  • Serine Proteases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2