Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2020 Apr 18

PMID 32302401

Citations 882

Authors

Betsy J Barnes

Jose M Adrover

Amelia Baxter-Stoltzfus

Alain Borczuk

Jonathan Cools-Lartigue

James M Crawford

Juliane Dassler-Plenker

Philippe Guerci

Caroline Huynh

Jason S Knight

Massimo Loda

Mark R Looney

Florencia McAllister

Roni Rayes

Stephane Renaud

Simon Rousseau

Steven Salvatore

Robert E Schwartz

Jonathan D Spicer

Christian C Yost

Andrew Weber

Yu Zuo

Mikala Egeblad

Affiliations

Soon will be listed here.

Abstract

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

Citing Articles

Neutrophils Display Novel Partners of Cytosolic Proliferating Cell Nuclear Antigen Involved in Interferon Response in COVID-19 Patients.

Pesenti L, de Oliveira Formiga R, Tamassia N, Gardiman E, Chable de La Heronniere F, Gasperini S J Innate Immun. 2025; 17(1):154-175.

PMID: 40015257 PMC: 11867639. DOI: 10.1159/000543633.

Harnessing Epigenetics: Innovative Approaches in Diagnosing and Combating Viral Acute Respiratory Infections.

Saha A, Ganguly A, Kumar A, Srivastava N, Pathak R Pathogens. 2025; 14(2).

PMID: 40005506 PMC: 11858160. DOI: 10.3390/pathogens14020129.

EpicPred: predicting phenotypes driven by epitope-binding TCRs using attention-based multiple instance learning.

Jeon J, Yu S, Lee S, Kim S, Jo H, Jung I Bioinformatics. 2025; 41(3).

PMID: 39982404 PMC: 11879650. DOI: 10.1093/bioinformatics/btaf080.

Bronchoalveolar lavage single-cell transcriptomics reveals immune dysregulations driving COVID-19 severity.

Asaba C, Bitazar R, Labonte P, Bukong T PLoS One. 2025; 20(2):e0309880.

PMID: 39928675 PMC: 11809808. DOI: 10.1371/journal.pone.0309880.

"The NET effect": Neutrophil extracellular traps-a potential key component of the dysregulated host immune response in sepsis.

Retter A, Singer M, Annane D Crit Care. 2025; 29(1):59.

PMID: 39905519 PMC: 11796136. DOI: 10.1186/s13054-025-05283-0.

References

Yost C, Schwertz H, Cody M, Wallace J, Campbell R, Vieira-de-Abreu A . Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest. 2016; 126(10):3783-3798. PMC: 5096809. DOI: 10.1172/JCI83873. View

Yao X, Li T, He Z, Ping Y, Liu H, Yu S . [A pathological report of three COVID-19 cases by minimal invasive autopsies]. Zhonghua Bing Li Xue Za Zhi. 2020; 49(5):411-417. DOI: 10.3760/cma.j.cn112151-20200312-00193. View

Schonrich G, Raftery M . Neutrophil Extracellular Traps Go Viral. Front Immunol. 2016; 7:366. PMC: 5027205. DOI: 10.3389/fimmu.2016.00366. View

Park J, Wysocki R, Amoozgar Z, Maiorino L, Fein M, Jorns J . Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci Transl Med. 2016; 8(361):361ra138. PMC: 5550900. DOI: 10.1126/scitranslmed.aag1711. View

Hawkins G, Robinson M, Hastie A, Li X, Li H, Moore W . The IL6R variation Asp(358)Ala is a potential modifier of lung function in subjects with asthma. J Allergy Clin Immunol. 2012; 130(2):510-5.e1. PMC: 3409329. DOI: 10.1016/j.jaci.2012.03.018. View

Ruan Q, Yang K, Wang W, Jiang L, Song J . Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46(5):846-848. PMC: 7080116. DOI: 10.1007/s00134-020-05991-x. View

Cedervall J, Zhang Y, Huang H, Zhang L, Femel J, Dimberg A . Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals. Cancer Res. 2015; 75(13):2653-62. DOI: 10.1158/0008-5472.CAN-14-3299. View

Adrover J, Aroca-Crevillen A, Crainiciuc G, Ostos F, Rojas-Vega Y, Rubio-Ponce A . Programmed 'disarming' of the neutrophil proteome reduces the magnitude of inflammation. Nat Immunol. 2020; 21(2):135-144. PMC: 7223223. DOI: 10.1038/s41590-019-0571-2. View

Ferreira R, Freitag D, Cutler A, Howson J, Rainbow D, Smyth D . Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013; 9(4):e1003444. PMC: 3617094. DOI: 10.1371/journal.pgen.1003444. View

10.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506. PMC: 7159299. DOI: 10.1016/S0140-6736(20)30183-5. View

11.

Oehmcke S, Morgelin M, Herwald H . Activation of the human contact system on neutrophil extracellular traps. J Innate Immun. 2010; 1(3):225-30. PMC: 6951039. DOI: 10.1159/000203700. View

12.

Sreeramkumar V, Adrover J, Ballesteros I, Cuartero M, Rossaint J, Bilbao I . Neutrophils scan for activated platelets to initiate inflammation. Science. 2014; 346(6214):1234-8. PMC: 4280847. DOI: 10.1126/science.1256478. View

13.

Raup-Konsavage W, Wang Y, Wang W, Feliers D, Ruan H, Reeves W . Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int. 2017; 93(2):365-374. PMC: 5794573. DOI: 10.1016/j.kint.2017.08.014. View

14.

Manzenreiter R, Kienberger F, Marcos V, Schilcher K, Krautgartner W, Obermayer A . Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy. J Cyst Fibros. 2011; 11(2):84-92. DOI: 10.1016/j.jcf.2011.09.008. View

15.

Kahlenberg J, Carmona-Rivera C, Smith C, Kaplan M . Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2012; 190(3):1217-26. PMC: 3552129. DOI: 10.4049/jimmunol.1202388. View

16.

Narasaraju T, Yang E, Perumal Samy R, Ng H, Poh W, Liew A . Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011; 179(1):199-210. PMC: 3123873. DOI: 10.1016/j.ajpath.2011.03.013. View

17.

Martinod K, Wagner D . Thrombosis: tangled up in NETs. Blood. 2013; 123(18):2768-76. PMC: 4007606. DOI: 10.1182/blood-2013-10-463646. View

18.

Meher A, Spinosa M, Davis J, Pope N, Laubach V, Su G . Novel Role of IL (Interleukin)-1β in Neutrophil Extracellular Trap Formation and Abdominal Aortic Aneurysms. Arterioscler Thromb Vasc Biol. 2018; 38(4):843-853. PMC: 5864548. DOI: 10.1161/ATVBAHA.117.309897. View

19.

Calabrese L, Rose-John S . IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014; 10(12):720-7. DOI: 10.1038/nrrheum.2014.127. View

20.

Mikacenic C, Moore R, Dmyterko V, West T, Altemeier W, Liles W . Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia. Crit Care. 2018; 22(1):358. PMC: 6307268. DOI: 10.1186/s13054-018-2290-8. View