Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology.
Crit Care
; 26(1): 206, 2022 07 07.
Article
in English
| MEDLINE | ID: covidwho-1923570
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
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Extracellular Traps
/
COVID-19 Drug Treatment
Limits:
Animals
Language:
English
Journal:
Crit Care
Year:
2022
Document Type:
Article
Affiliation country:
S13054-022-04062-5
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