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

了解 COVID-19 中中性粒细胞胞外陷阱 (NET) 的形成

• 批准号: 458740561
• 负责人: Professorin Dr. Luise Erpenbeck
• 金额: --
• 依托单位: Klinik für Hautkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/458740561?language=en
• 关键词: Understanding; Neutrophil; Extracellular; Trap; NET

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.

中性粒细胞活化和中性粒细胞胞外陷阱（NETs）的过度形成正在成为严重COVID-19的标志。这种免疫防御机制的失调可能导致细胞因子风暴，并导致COVID-19患者的高凝血症和肺损伤。然而，很少有人了解NET的形成是如何调节或失调，在这种疾病。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活化。此外，将使用活细胞显微镜研究SARS-CoV-2诱导的NET形成以及COVID-19患者血浆诱导的NET。我们还将测试COVID-19患者的中性粒细胞是否通常具有更高的NET形成倾向。尽管嗜中性粒细胞和过量的NET形成似乎主要与COVID-19患者的不良结局相关，但可以想象，适度和良好调节的NET形成量有利于控制疾病，因为NET已被描述为具有抗病毒特性。因此，我们还将研究SARS-CoV-2是否可以通过与NET结合而被固定和中和。最后，我们将确定抑制COVID-19中不受控制的NET形成的药理学靶点，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疗法。