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

Author(s):Show less -

Veras, Flavio Protasio ^{[1, 2]} ; Pontelli, Marjorie Cornejo ^{[3, 4]} ; Silva, Camila Meirelles ^{[1, 2]} ; Toller-Kawahisa, Juliana E. ^{[1, 2]} ; de Lima, Mikhael ^{[1, 2]} ; Nascimento, Daniele Carvalho ^{[1, 2]} ; Schneider, Ayda Henriques ^{[1, 2]} ; Caetite, Diego ^{[1, 2]} ; Tavares, Lucas Alves ^{[3, 4]} ; Paiva, Isadora M. ^{[1, 2]} ; Rosales, Roberta ^[3] ; Colon, David ^{[1, 2]} ; Martins, Ronaldo ^{[3, 4]} ; Castro, Italo Araujo ^{[3, 4]} ; Almeida, Glaucia M. ^{[1, 2]} ; Fernandes Lopes, Maria Isabel ^{[5, 6, 7, 8]} ; Benatti, Maira Nilson ^{[5, 6, 7, 8]} ; Bonjorno, Leticia Pastorelli ^{[5, 6, 7, 8]} ; Giannini, Marcela Cavichioli ^{[5, 6, 7, 8]} ; Luppino-Assad, Rodrigo ^{[5, 6, 7, 8]} ; Almeida, Sergio Luna ^{[5, 6, 7, 8]} ; Vilar, Fernando ^{[5, 6, 7, 8]} ; Santana, Rodrigo ^{[5, 6, 7, 8]} ; Bollela, Valdes R. ^{[5, 6, 7, 8]} ; Auxiliadora-Martins, Maria ^{[5, 6, 7, 8]} ; Borges, Marcos ^{[5, 6, 7, 8]} ; Miranda, Carlos Henrique ^{[5, 6, 7, 8]} ; Pazin-Filho, Antonio ^{[5, 6, 7, 8]} ; da Silva, Luis Lamberti P. ^{[3, 4]} ; Cunha, Larissa Dias ^[3] ; Zamboni, Dario S. ^{[3, 2]} ; Dal-Pizzol, Felipe ^[9] ; Leiria, Luiz O. ^{[1, 2]} ; Siyuan, Li ; Batah, Sabrina ^[10] ; Fabro, Alexandre ^[10] ; Mauad, Thais ^[11] ; Dolhnikoff, Marisa ^[11] ; Duarte-Neto, Amaro ^[11] ; Saldiva, Paulo ^[11] ; Cunha, Thiago Mattar ^{[1, 2]} ; Alves-Filho, Jose Carlos ^{[1, 2]} ; Arruda, Eurico ^{[3, 4]} ; Louzada-Junior, Paulo ^{[2, 5, 6, 7, 8]} ; Oliveira, Rene Donizeti ^{[5, 6, 7, 8]} ; Cunha, Fernando Queiroz ^{[1, 2]}

Affiliation:Show less -

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ctr Res Inflammatory Dis, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell & Mol Biol, Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Virol Res Ctr, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Div Clin Immunol, Ribeirao Preto, SP - Brazil

^[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Div Emergency, Ribeirao Preto, SP - Brazil

^[7] Univ Sao Paulo, Ribeirao Preto Med Sch, Div Infect Dis, Ribeirao Preto, SP - Brazil

^[8] Univ Sao Paulo, Ribeirao Preto Med Sch, Div Intens Care Unit, Ribeirao Preto, SP - Brazil

^[9] Univ Southern Santa Catarina, Hlth Sci Unit, Lab Expt Pathophysiol, Grad Program Hlth Sci, Criciuma, SC - Brazil

^[10] Li Siyuan, Univ Sao Paulo, Ribeirao Preto Med Sch, Pathol & Legal Med, Ribeirao Preto, SP - Brazil

^[11] Univ Sao Paulo, Sch Med, Dept Pathol, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF EXPERIMENTAL MEDICINE; v. 217, n. 12 DEC 2020.
• Web of Science Citations: 15

Abstract

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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/05601-6 - Neutrophil extracelular traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID-19
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Regular Research Grants