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

中性粒细胞激活和中性粒细胞胞外陷阱(NETs)的过度形成正在成为严重新冠肺炎的特征。这种免疫防御机制的失调可能导致细胞因子风暴，并导致新冠肺炎患者的高凝血症和肺损伤。然而，关于净形成在这种疾病中是如何调节或失调的，人们知之甚少。因此，我们将评估中性粒细胞是否能够与SARS-CoV-2直接相互作用，以及这种相互作用是否导致中性粒细胞摄取病毒、病毒复制和中性粒细胞激活。此外，还将使用活细胞显微镜研究SARS-CoV-2诱导的网络形成以及新冠肺炎患者血浆对网络的诱导。我们还将测试新冠肺炎患者的中性粒细胞是否通常有更高的净形成倾向。虽然中性粒细胞增多和过度的网状物形成似乎主要与新冠肺炎患者的不良预后有关，但可以想象，适度和良好调节的网状物形成量对于控制疾病是有益的，因为Net被描述为具有抗病毒特性。因此，我们亦会研究SARS-CoV-2能否透过与母语英语教师的结合而被固定和中和。最后，我们将确定抑制新冠肺炎失控网络形成的药理学目标，长期目标是开发适用于患有该疾病和其他严重感染的人类患者的治疗方法。

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.