Understanding Neutrophil Extracellular Trap (NET) formation in COVID-19

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Neutrophil activation and excessive formation of neutrophil extracellular traps (NETs) is emerging as a hallmark of severe COVID-19. Dysregulation of this immune defense mechanism can contribute to the cytokine storm and cause hypercoagulopathy and lung injury in COVID-19 patients. However, little is understood about how NET formation is regulated or dysregulated in this disease. Therefore, we will assess whether neutrophils are able to directly interact with SARS-CoV-2 and whether this interaction leads to virus uptake by neutrophils, virus replication and neutrophil activation. Additionally, SARS-CoV-2-induced NET formation as well as the induction of NETs by COVID-19 patient plasma will be studied using live-cell microscopy. We will also test whether neutrophils from COVID-19 patients generally have a higher propensity for NET formation. Although neutrophilia and excessive NET formation appears to be mainly associated with a poor outcome in COVID-19 patients, it is conceivable that a moderate and well-regulated amount of NET formation is beneficial for controlling the disease as NETs have been described to possess antiviral properties. Therefore, we will also investigate whether SARS-CoV-2 can be immobilised and neutralised by binding to NETs. Finally, we will identify pharmacological targets to inhibit uncontrolled NET formation in COVID-19 with the long-term goal of developing therapies applicable in human patients suffering from the disease and from other severe infections.