RESUMO
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 BriefHere, 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.
RESUMO
Two Alphaviruses stand out for their clinical importance in Brazil: chikungunya (CHIKV) and mayaro (MAYV) viruses. Few studies exist on the mechanisms of the immune response after infection by these viruses and neither a treatment nor a vaccine for these pathogens are available. Although their infection does not have a high mortality rate, they can lead to a joint involvement that can persist for months. The aims of this work were the study of the mechanisms of antiviral immune response following in vitro (U937 cells) infection with these viruses; to investigate the characteristics of the infection by these viruses; and to determine possible molecular targets that could serve as antiviral therapies against these pathogens. Several genes were modulated after infection by these viruses, and the three antiviral detection and response pathways were activated (Toll-like, RIG-I and NOD-like). Eotaxin and IL-6 were induced in all experiments. The cellular immune response profile found for each virus was different, with CHIKV activating primarily an inflammatory response (Th1 and Th17) and MAYV inducing a regulatory/suppressive response, an important feature to contain the inflammation resulting from infection. The data acquired by this study could provide an explanation why CHIKV infections, due to activation of the inflammatory response, are more clinically relevant than MAYV infections, which generates mostly an anti-inflammatory response after infection.
