Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

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.

Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis

“…24 Moreover, AAT has regulatory roles in the coagulation cascade 25 and, via elastase inhibition, could inhibit NET-triggered immunothromboses. 26 Notably, inflammatory dysregulation and coagulopathies have been reported to play a role in the disparate COVID-19 severities between patients. 27 The potent neutralization of protease-mediated cellular entry by SARS-CoV-2 along with the wide range and prevalence of functionally different AAT genotypes implies a potential role for AAT in variable COVID-19 severity.…”

The Trans-omics Landscape of COVID-19

“…However, excessively activated neutrophils form neutrophil extracellular traps (NETs) and lead to tissue damage, which is termed NETosis, as we found in critically ill COVID-19 patients. NETs are closely related to the severity of in uenza, Ebola virus infection, and COVID-19 43,63 . These observations hint at a prominent role of neutrophils in COVID-19.…”

“…Especially during severe viral infections, neutrophils may abnormally differentiate to pathological low-density neutrophils (LDNs) with an enhanced capacity to release neutrophil extracellular traps (NETs) 42 . Excessive NETs release cause endothelium damage, promote thrombosis, and contribute to mortality in COVID-19 43 . As we showed in Fig.…”

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

“…149 In addition, the severity of COVID-19 correlates directly with plasma myeloperoxidase (MPO)-DNA complexes (NETs). 150 Self-DNA release due to cellular stress or tissue damage after SARS-CoV-2 infection could potentially activate the cGAS-STING pathway, leading to excessive production of the type 1 interferon and inflammatory cytokines, and contributing to the severity of COVID-19. Investigating the role of the cGAS-STING pathway in the pathogenesis of COVID-19 may provide a potential therapeutic strategy.…”