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

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Abstract

The knowledge of COVID-19 pathophysiology is pivotal for the discovery of effective treatments. Here, we described that SARS-CoV-2 triggers the release of ACE2-depended neutrophil extracellular traps (NETs) that mediate lung pathology, supporting the use of NETs inhibitors for COVID-19 treatment.

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.

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Most cited references 42

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Author and article information

Contributors

Flavio Protasio Veras:

ORCID: https://orcid.org/0000-0002-6222-4064

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Marjorie Cornejo Pontelli:

ORCID: https://orcid.org/0000-0003-3173-5977

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing - original draft

Camila Meirelles Silva:

ORCID: https://orcid.org/0000-0001-8185-4435

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Validation

Juliana E. Toller-Kawahisa:

ORCID: https://orcid.org/0000-0001-7323-5036

Role: InvestigationRole: MethodologyRole: Validation

Mikhael de Lima:

ORCID: https://orcid.org/0000-0002-9377-0340

Role: Formal analysisRole: InvestigationRole: Writing - original draftRole: Writing - review & editing

Daniele Carvalho Nascimento:

ORCID: https://orcid.org/0000-0002-0620-339X

Role: InvestigationRole: MethodologyRole: Validation

Ayda Henriques Schneider:

ORCID: https://orcid.org/0000-0003-2474-2773

Role: InvestigationRole: MethodologyRole: Validation

Diego Caetité:

ORCID: https://orcid.org/0000-0003-3916-6748

Role: InvestigationRole: MethodologyRole: Validation

Lucas Alves Tavares:

ORCID: https://orcid.org/0000-0001-7883-1443

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Isadora M. Paiva:

ORCID: https://orcid.org/0000-0002-2741-150X

Role: MethodologyRole: Validation

Roberta Rosales:

ORCID: https://orcid.org/0000-0001-7790-2983

Role: Data curationRole: Formal analysisRole: Visualization

David Colón:

ORCID: https://orcid.org/0000-0002-6911-4765

Role: Investigation

Ronaldo Martins:

ORCID: https://orcid.org/0000-0002-8902-5962

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Italo Araujo Castro:

ORCID: https://orcid.org/0000-0001-7885-7547

Role: InvestigationRole: ResourcesRole: ValidationRole: Visualization

Glaucia M. Almeida:

ORCID: https://orcid.org/0000-0003-4149-5313

Role: Methodology

Maria Isabel Fernandes Lopes:

ORCID: https://orcid.org/0000-0002-5060-4289

Role: Data curationRole: Resources

Maíra Nilson Benatti:

ORCID: https://orcid.org/0000-0002-8067-267X

Role: Resources

Letícia Pastorelli Bonjorno:

ORCID: https://orcid.org/0000-0003-2459-423X

Role: Data curationRole: Resources

Marcela Cavichioli Giannini:

ORCID: https://orcid.org/0000-0003-2859-2055

Role: Data curationRole: Investigation

Rodrigo Luppino-Assad:

ORCID: https://orcid.org/0000-0002-8430-8357

Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - review & editing

Sérgio Luna Almeida:

ORCID: https://orcid.org/0000-0002-1787-4797

Role: InvestigationRole: Resources

Fernando Vilar:

ORCID: https://orcid.org/0000-0001-8232-5375

Role: InvestigationRole: Writing - review & editing

Rodrigo Santana:

ORCID: https://orcid.org/0000-0002-5887-8663

Role: InvestigationRole: ResourcesRole: Writing - review & editing

Valdes R. Bollela:

ORCID: https://orcid.org/0000-0002-8221-4701

Role: ConceptualizationRole: InvestigationRole: Project administrationRole: Visualization

Maria Auxiliadora-Martins:

ORCID: https://orcid.org/0000-0003-3923-4464

Role: Resources

Marcos Borges:

ORCID: https://orcid.org/0000-0001-6280-0714

Role: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Carlos Henrique Miranda:

ORCID: https://orcid.org/0000-0002-5968-4879

Role: ResourcesRole: SupervisionRole: Writing - review & editing

Antônio Pazin-Filho:

ORCID: https://orcid.org/0000-0001-5242-329X

Role: Project administrationRole: ResourcesRole: VisualizationRole: Writing - original draft

Luis Lamberti P. da Silva:

ORCID: https://orcid.org/0000-0003-3558-0087

Role: MethodologyRole: ResourcesRole: SupervisionRole: Writing - review & editing

Larissa Cunha:

ORCID: https://orcid.org/0000-0002-1290-0263

Role: MethodologyRole: ResourcesRole: Writing - review & editing

Dario S. Zamboni:

ORCID: https://orcid.org/0000-0002-7856-7512

Role: ConceptualizationRole: Writing - review & editing

Felipe Dal-Pizzol:

ORCID: https://orcid.org/0000-0003-3003-8977

Role: Formal analysisRole: InvestigationRole: ResourcesRole: Writing - review & editing

Luiz O. Leiria:

ORCID: https://orcid.org/0000-0001-9483-3705

Role: ConceptualizationRole: SupervisionRole: Writing - original draftRole: Writing - review & editing

Li Siyuan:

ORCID: https://orcid.org/0000-0002-8136-1021

Role: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Visualization

Sabrina Batah:

ORCID: https://orcid.org/0000-0002-9694-3489

Role: Resources

Alexandre Fabro:

ORCID: https://orcid.org/0000-0002-7687-3161

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Thais Mauad:

ORCID: https://orcid.org/0000-0002-3354-1466

Role: MethodologyRole: Writing - review & editing

Marisa Dolhnikoff:

ORCID: https://orcid.org/0000-0002-9073-9989

Role: Investigation

Amaro Duarte-Neto:

ORCID: https://orcid.org/0000-0001-6659-7186

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing - review & editing

Paulo Saldiva:

ORCID: https://orcid.org/0000-0003-2005-8253

Role: Data curationRole: MethodologyRole: Supervision

Thiago Mattar Cunha:

ORCID: https://orcid.org/0000-0003-1084-0065

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing

José Carlos Alves-Filho:

ORCID: https://orcid.org/0000-0002-9918-8714

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Writing - original draftRole: Writing - review & editing

Eurico Arruda:

ORCID: https://orcid.org/0000-0002-0978-410X

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: Writing - review & editing

Paulo Louzada-Junior:

ORCID: https://orcid.org/0000-0003-2585-3870

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: SupervisionRole: ValidationRole: Writing - review & editing

Renê Donizeti Oliveira:

ORCID: https://orcid.org/0000-0003-0229-6864

Role: ConceptualizationRole: Data curationRole: InvestigationRole: VisualizationRole: Writing - review & editing

Fernando Queiroz Cunha:

ORCID: https://orcid.org/0000-0003-4755-1670

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (publisher-id): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 07 December 2020

Publication date (Electronic): 14 September 2020

Publication date PMC-release: 14 September 2020

Volume: 217

Issue: 12

Electronic Location Identifier: e20201129

Affiliations

[1 ]Center of Research in Inflammatory Diseases, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[2 ]Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[3 ]Virology Research Center, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[4 ]Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[5 ]Divisions of Clinical Immunology, Emergency, Infectious Diseases and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[6 ]Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

[7 ]Department Pathology, School of Medicine, University of São Paulo, São Paulo, Brazil

[8 ]Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Santa Catarina, Brazil

Author notes

Correspondence to Fernando Q. Cunha: fdqcunha@ 123456fmrp.usp.br

Flavio P. Veras: fprotasio@ 123456usp.br

Thiago Mattar Cunha: thicunha@ 123456fmrp.usp.br

Disclosures: The authors declare no competing interests exist.

Author information

Flavio Protasio Veras https://orcid.org/0000-0002-6222-4064

Marjorie Cornejo Pontelli https://orcid.org/0000-0003-3173-5977

Camila Meirelles Silva https://orcid.org/0000-0001-8185-4435

Juliana E. Toller-Kawahisa https://orcid.org/0000-0001-7323-5036

Mikhael de Lima https://orcid.org/0000-0002-9377-0340

Daniele Carvalho Nascimento https://orcid.org/0000-0002-0620-339X

Ayda Henriques Schneider https://orcid.org/0000-0003-2474-2773

Diego Caetité https://orcid.org/0000-0003-3916-6748

Lucas Alves Tavares https://orcid.org/0000-0001-7883-1443

Isadora M. Paiva https://orcid.org/0000-0002-2741-150X

Roberta Rosales https://orcid.org/0000-0001-7790-2983

David Colón https://orcid.org/0000-0002-6911-4765

Ronaldo Martins https://orcid.org/0000-0002-8902-5962

Italo Araujo Castro https://orcid.org/0000-0001-7885-7547

Glaucia M. Almeida https://orcid.org/0000-0003-4149-5313

Maria Isabel Fernandes Lopes https://orcid.org/0000-0002-5060-4289

Maíra Nilson Benatti https://orcid.org/0000-0002-8067-267X

Letícia Pastorelli Bonjorno https://orcid.org/0000-0003-2459-423X

Marcela Cavichioli Giannini https://orcid.org/0000-0003-2859-2055

Rodrigo Luppino-Assad https://orcid.org/0000-0002-8430-8357

Sérgio Luna Almeida https://orcid.org/0000-0002-1787-4797

Fernando Vilar https://orcid.org/0000-0001-8232-5375

Rodrigo Santana https://orcid.org/0000-0002-5887-8663

Valdes R. Bollela https://orcid.org/0000-0002-8221-4701

Maria Auxiliadora-Martins https://orcid.org/0000-0003-3923-4464

Marcos Borges https://orcid.org/0000-0001-6280-0714

Carlos Henrique Miranda https://orcid.org/0000-0002-5968-4879

Antônio Pazin-Filho https://orcid.org/0000-0001-5242-329X

Luis Lamberti P. da Silva https://orcid.org/0000-0003-3558-0087

Larissa Cunha https://orcid.org/0000-0002-1290-0263

Dario S. Zamboni https://orcid.org/0000-0002-7856-7512

Felipe Dal-Pizzol https://orcid.org/0000-0003-3003-8977

Luiz O. Leiria https://orcid.org/0000-0001-9483-3705

Li Siyuan https://orcid.org/0000-0002-8136-1021

Sabrina Batah https://orcid.org/0000-0002-9694-3489

Alexandre Fabro https://orcid.org/0000-0002-7687-3161

Thais Mauad https://orcid.org/0000-0002-3354-1466

Marisa Dolhnikoff https://orcid.org/0000-0002-9073-9989

Amaro Duarte-Neto https://orcid.org/0000-0001-6659-7186

Paulo Saldiva https://orcid.org/0000-0003-2005-8253

Thiago Mattar Cunha https://orcid.org/0000-0003-1084-0065

José Carlos Alves-Filho https://orcid.org/0000-0002-9918-8714

Eurico Arruda https://orcid.org/0000-0002-0978-410X

Paulo Louzada-Junior https://orcid.org/0000-0003-2585-3870

Renê Donizeti Oliveira https://orcid.org/0000-0003-0229-6864

Fernando Queiroz Cunha https://orcid.org/0000-0003-4755-1670

Article

Publisher ID: jem.20201129

DOI: 10.1084/jem.20201129

PMC ID: 7488868

PubMed ID: 32926098

SO-VID: 00886f6b-a8a3-4a16-bbd4-f5694e2338f7

License:

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 06 June 2020

Date revision received : 11 August 2020

Date accepted : 31 August 2020

Page count

Pages: 12

Funding

Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo, DOI http://dx.doi.org/10.13039/501100001807;

Award ID: 2013/08216-2

Award ID: 2020/05601-6

Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico, DOI http://dx.doi.org/10.13039/501100003593;

Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, DOI http://dx.doi.org/10.13039/501100002322;

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

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Novel Coronavirus Disease COVID-19

Most cited references 42

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

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