Gasdermin-D activation by SARS-CoV-2 trigger NET and mediate COVID-19 immunopathology

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. Using a single-cell transcriptome analysis we observed that the expression of GSDMD and inflammasome-related genes were increased in neutrophils from COVID-19 patients. Furthermore, high expression of GSDMD was found associated with NETs structures in the lung tissue of COVID-19 patients. The activation of GSDMD in neutrophils requires live SARS-CoV-2 and occurs after neutrophil infection via ACE2 receptors and serine protease TMPRSS2. In a mouse model of SARS-CoV-2 infection, the treatment with GSDMD inhibitor (disulfiram) reduced NETs release and organ damage. These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology, and suggests that GSDMD inhibitors, can be useful to COVID-19 treatment. In Brief Here, we showed that the activation of the Gasdermin-D (GSDMD) pathway in neutrophils controls NET release during COVID-19. The inhibition of GSDMD with disulfiram, abrogated NET formation reducing lung inflammation and tissue damage. These findings suggest GSDMD as a target for improving the COVID-19 therapy.