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

• Published in: The Journal of experimental medicine Vol. 217; no. 12
• Main Authors: Veras, Flavio Protasio, Pontelli, Marjorie Cornejo, Silva, Camila Meirelles, Toller-Kawahisa, Juliana E., de Lima, Mikhael, Nascimento, Daniele Carvalho, Schneider, Ayda Henriques, Caetité, Diego, Tavares, Lucas Alves, Paiva, Isadora M., Rosales, Roberta, Colón, David, Martins, Ronaldo, Castro, Italo Araujo, Almeida, Glaucia M., Lopes, Maria Isabel Fernandes, Benatti, Maíra Nilson, Bonjorno, Letícia Pastorelli, Giannini, Marcela Cavichioli, Luppino-Assad, Rodrigo, Almeida, Sérgio Luna, Vilar, Fernando, Santana, Rodrigo, Bollela, Valdes R., Auxiliadora-Martins, Maria, Borges, Marcos, Miranda, Carlos Henrique, Pazin-Filho, Antônio, da Silva, Luis Lamberti P., Cunha, Larissa Dias, Zamboni, Dario S., Dal-Pizzol, Felipe, Leiria, Luiz O., Siyuan, Li, Batah, Sabrina, Fabro, Alexandre, Mauad, Thais, Dolhnikoff, Marisa, Duarte-Neto, Amaro, Saldiva, Paulo, Cunha, Thiago Mattar, Alves-Filho, José Carlos, Arruda, Eurico, Louzada-Junior, Paulo, Oliveira, Renê Donizeti, Cunha, Fernando Queiroz
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.12.2020
• Subjects: A549 Cells; Adult; Angiotensin-Converting Enzyme 2; Betacoronavirus - physiology; Brief Definitive Report; Cell Death; Coronavirus Infections - blood; Coronavirus Infections - immunology; Coronavirus Infections - pathology; Coronavirus Infections - virology; COVID-19; Epithelial Cells - pathology; Epithelial Cells - virology; Extracellular Traps - physiology; Female; HeLa Cells; Humans; Innate Immunity and Inflammation; 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
• ISSN: 0022-1007; 1540-9538; 1540-9538
• 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.