Abstract
Background: The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.
Objectives: We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.
Methods: We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.
Results: We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.
Conclusion: These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
Keywords: COVID-19; Innate immunity; NETs; Neutrophil; Organ damage.
【저자키워드】 COVID-19, Innate immunity, neutrophil, NETs, Organ damage., 【초록키워드】 Treatment, Transcriptome, Neutrophils, Structure, Inflammation, severe COVID-19, Neutrophil extracellular traps, SARS-COV-2 infection, neutrophil, SARS-CoV-2 virus, immunopathology, molecular mechanism, disulfiram, Coagulopathy, Protein, pathway, severe cases, Neutrophil extracellular trap, NETosis, Inflammasome, signaling pathway, mouse model, expression, Critical, moderate, NETs, single-cell, therapeutic strategy, COVID-19 patients, Blood, Bronchoalveolar lavage, Analysis, Innate, Pathways, Trigger, triggers, Activation, molecular mechanisms, Severe case, live SARS-CoV-2, lung tissue, organ damage, infect, NET, GSDMD, enrolled, analyzed, performed, inhibited, reduced, hospitalized patient, demonstrated, activate, lung tissue sample, the SARS-CoV-2 virus, 【제목키워드】 SARS-CoV-2, Trigger, Activation, NET,