Targeting potential drivers of COVID-19: Neutrophil extracellular traps

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, 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

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.

Conflict of interest statement

Disclosures: M.R. Looney reported "other" from Neutrolis outside the submitted work. R.E. Schwartz is a Sponsored Advisory Board Member for Miromatrix Inc. J.D. Spicer reported personal fees from Bristol Myers Squibb, personal fees from Astra Zeneca, personal fees from Merck, personal fees from Trans-Hit Bio, and non-financial support from Astra Zeneca outside the submitted work. C.C. Yost reports a grant from PEEL Therapeutics, Inc. during the conduct of the study; in addition, C.C. Yost authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for "treatment of and prophylaxis against inflammatory disorders." PEEL Therapeutics, Inc. has exclusive licensing rights. M. Egeblad reported "other" from Santhera during the conduct of the study; and consulted for CytomX in 2019. No other disclosures were reported.

© 2020 Barnes et al.

Figures

Figure 1.
Figure 1.
Neutrophils in an autopsy specimen from the lungs of a patient who succumbed from COVID-19.(A) Extensive neutrophil infiltration in pulmonary capillaries, with acute capillaritis with fibrin deposition, and extravasation into the alveolar space. An image was chosen to emphasize the capillary lesions. (B) Neutrophilic mucositis of the trachea. The entire airway was affected (images by A. Borczuk, Weill Cornell Medical Center). Both specimens originate from a 64-yr-old male of Hispanic decent with diabetes, end-stage renal disease on hemodialysis, heart failure, and hepatitis C on ledipasvir/sofosbuvir therapy. He declined medical intervention, was therefore not intubated, and died in the emergency room 5 h after presentation, shortly after developing fever. There was no evidence of sepsis in this patient clinically, premortem cultures were negative, and the autopsy was performed within 5 h of death. Similar neutrophil distribution, but with less extensive infiltration, was observed in the two additional autopsies analyzed to date. These other two cases had longer duration of symptoms. Scale bars: 50 µm.
Figure 2.
Figure 2.
Neutrophils forming NETs in cell culture. Note the expelled DNA strings (arrows). Scanning electron microscopy of neutrophils 3 h after plating and coculturing with 4T1 breast cancer cells. Scale bar: 25 µm.
Figure 3.
Figure 3.
Excess NET formation can drive a variety of severe pathologies. In the lungs, NETs drive the accumulation of mucus in CF patients’ airways. NETs also drive ARDS after a variety of inducers, including influenza. In the vascular system, NETs drive atherosclerosis and aortic aneurysms, as well as thrombosis (particularly microthrombosis), with devastating effects on organ function.
Figure 4.
Figure 4.
Approaches to targeting NETs. NETs can be targeted by existing drugs through several means. NE, PAD4, and gasdermin D inhibitors will prevent NET formation. DNase has been used safely to digest NETs in the mucous secretions of the airways of CF patients. Colchicine inhibits neutrophil migration and infiltration into sites of inflammation. IL1β blockers will prevent an inflammatory loop between NETs and IL1β. Of these approaches, trials to treat COVID-19 with colchicine and anakinra are already ongoing or being launched (ClinicalTrials.gov identifiers: NCT04324021, NCT04330638, NCT02735707, NCT04326790, NCT04328480, NCT04322565, NCT04322682).

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