Neutrophil Extracellular Traps in COVID-19 Pathophysiology

Neutrophil extracellular traps (NETs) are web-like assemblies of decondensed chromatin decorated with antimicrobial proteins that neutrophils release to immobilise pathogens. In severe COVID-19, disproportionate NET formation and impaired clearance contribute to immunothrombotic complications, acute respiratory distress syndrome and multiorgan dysfunction. Excessive NETosis fosters platelet aggregation, endothelial injury and microvascular thrombosis, driving respiratory failure and systemic inflammation. Concurrently, reduced enzymatic degradation of NETs by circulating DNases sustains tissue damage. An array of factors—including cross-reactive antibodies, platelet-derived microRNAs and inflammatory mediators—amplify NETosis in COVID-19, while emerging treatments targeting the ROS–NET axis, DNase supplementation and receptor blockade offer promising strategies to mitigate immunothrombosis and improve clinical outcomes on a global scale.

Research from Nature Portfolio

A foundational study first demonstrated that SARS-CoV-2 directly triggers NETosis in human neutrophils by inducing intracellular reactive oxygen species, linking viral exposure to extracellular trap formation and enhanced thrombogenic potential. This work established the ROS–NET pathway as a critical mediator of COVID-19 immunothrombosis and suggested that antioxidants or inhibitors of oxidative burst may attenuate NET-driven vascular injury. A subsequent large-scale proteomic analysis identified a biomarker panel including the neutrophil-derived proteins S100A8/A9 (calprotectin), thrombospondin-1 and fibronectin that predicts progression to severe disease in early infection. Elevated levels of these proteins in plasma reflect heightened neutrophil activation and potential NET release, underscoring the value of NET-associated markers for early stratification and guiding therapeutic intervention.

Neutrophil Extracellular Traps in COVID-19 Pathophysiology publication trend

The graph below shows the total number of articles in neutrophil extracellular traps in covid-19 pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil extracellular traps (NETs): Meshes of DNA, histones and antimicrobial proteins expelled by neutrophils to trap and neutralise pathogens.

NETosis: Programmed cell death mechanism in neutrophils culminating in the release of NETs.

Reactive oxygen species (ROS): Chemically reactive molecules produced during respiratory burst that facilitate NETosis.

DNases: Enzymes (e.g., DNase1 and DNase1L3) that degrade NET DNA and regulate trap clearance.

Extracellular vesicles (EVs): Nano-sized membrane-bound particles carrying proteins and RNAs that mediate intercellular communication.

References

1. Neutrophil extracellular traps in COVID-19. JCI Insight (2020).
2. Discovery and systematic assessment of early biomarkers that predict progression to severe COVID-19 disease. Communications Medicine (2023).
3. Enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19. Journal of Biomedical Science (2024).
4. SARS-CoV-2 primed platelets–derived microRNAs enhance NETs formation by extracellular vesicle transmission and TLR7/8 activation. Cell Communication and Signaling (2023).
5. Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease. Journal of Translational Medicine (2024).