Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Barnes, Betsy J.; Adrover, Jose M.; Baxter-Stoltzfus, Amelia; Borczuk, Alain; Cools-Lartigue, Jonathan; Crawford, James M.; Daßler-Plenker, Juliane; Guerci, Philippe; Huynh, Caroline; Knight, Jason S.; Loda, Massimo; Looney, Mark R.; McAllister, Florencia; Rayes, Roni; Renaud, Stephane; Rousseau, Simon; Salvatore, Steven; Schwartz, Robert E.; Spicer, Jonathan D.; Yost, Christian C.; Weber, Andrew; Zuo, Yu; Egeblad, Mikala

Prior reports extensively link aberrant NET formation to pulmonary diseases, particularly ARDS. Indeed, NET levels in plasma are higher in patients with transfusion-associated ARDS than in subjects without ARDS (Caudrillier et al., 2012) . Furthermore, neutrophils from patients with pneumonia-associated ARDS appear "primed" to form NETs, and both the extent of priming and the level of NETs in blood correlate with disease severity and mortality (Adrover et al., 2020; Bendib et al., 2019; Ebrahimi et al., 2018; Lefrançais et al., 2018; Mikacenic et al., 2018) . Extracellular histones, likely partly originating from NETs, are elevated in the bronchoalveolar lavage fluid and plasma of ARDS patients (Lv et al., 2017) . Naked histones are toxic to cells, and there is strong experimental evidence supporting a role for histones in ARDS and sepsis (Wygrecka et al., 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. . 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. 2017; Xu et al., 2015) . It is therefore likely that NETs, as a source of extracellular histones, contribute to ARDS and sepsis (Chaput and Zychlinsky, 2009; Lefrançais and Looney, 2017; Xu et al., 2009) . In animal models of lung injury, NETs develop in response to a variety of ARDS-inducing stimuli, and preventing or dissolving NETs reduces lung injury and increases survival (Caudrillier et al., 2012; Lefrançais et al., 2018; Liu et al., 2016; Narasaraju et al., 2011) .