Journal
CRITICAL CARE
Volume 26, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13054-022-04062-5
Keywords
Neutrophil; Innate immunity; Organ damage; COVID-19; NETs
Categories
Funding
- Sao Paulo Research Foundation (FAPESP) [2013/08216-2]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
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This study reveals that SARS-CoV-2 virus directly activates GSDMD, leading to the production of NETs and organ damage in COVID-19. Single-cell transcriptome analysis shows increased expression of GSDMD and inflammasome-related genes in COVID-19 patients. Treatment with disulfiram inhibits NETs release and reduces organ damage in a mouse model of SARS-CoV-2 infection.
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.
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