Neutrophil Extracellular Traps (NETs) Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome

Middleton, EA, He, X.-Y., Denorme, F, Campbell, RA, Ng, D., Salvatore, S., Mostyka, M, Baxter-Stoltzfus, A., Borczuk, A., Loda, M., Cody, MJ, Manne, BK, Portier, I, Harris, E, Petrey, AC, Beswick, EJ, Caulin, AF, Iovino, A, Abegglen, LM, Weyrich, AS, Rondina, MT, Egeblad, M., Schiffman, JD, Con Yost, C (June 2020) Neutrophil Extracellular Traps (NETs) Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome. Blood. ISSN 0006-4971

URL: https://pubmed.ncbi.nlm.nih.gov/32597954/
DOI: 10.1182/blood.2020007008

Abstract

COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n=33) with age- and sex-matched controls (n=17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), Platelet Factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-Inhibitory Factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19 with intubation (P<0.0001) and death as outcome (P<0.0005). Illness severity correlated directly with plasma MPO-DNA complexes (P=0.0360), while PaO2/FiO2 correlated inversely(P=0.0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19 and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline and COVID-19 plasma triggered NET formation which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19 and NETs may represent targets for therapeutic intervention.

Item Type: Paper
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Matthew Dunn
Date: 29 June 2020
Date Deposited: 06 Jul 2020 20:52
Last Modified: 26 Oct 2020 15:53
URI: https://repository.cshl.edu/id/eprint/39512

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