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

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Silva, Camila Meirelles S. ; Wanderley, Carlos Wagner S. ; Veras, Flavio Protasio ; Goncalves, Augusto Veloso ; Fernandes Lima, Mikhael Haruo ; Toller Kawahisa, Juliana Escher ; Gomes, Giovanni Freitas ; Nascimento, Daniele Carvalho ; Silva Monteiro, Valter V. ; Paiva, Isadora Marques ; Luiz Ramos Almeida, Cicero Jose ; Caetite, Diego Brito ; Silva, Juliana Costa ; Fernandes Lopes, Maria Isabel ; Bonjorno, Leticia Pastorelli ; Giannini, Marcela Cavichioli ; Amaral, Natalia Brasil ; Benatti, Maira Nilson ; Santana, Rodrigo Carvalho ; Alves Damasceno, Luis Eduardo ; Souza Silva, Bruna Manuella ; Schneider, Ayda Henriques ; Santos Castro, Icaro Maia ; Santos Silva, Juan Carlo ; Vasconcelos, Amanda Pereira ; Goncalves, Tiago Tomazini ; Batah, Sabrina Setembre ; Rodrigues, Tamara Silva ; Costa, Victor Ferreira ; Pontelli, Marjorie Cornejo ; Martins, Ronaldo B. ; Martins, Timna Varela ; Alves Esposito, Danillo Lucas ; Martelossi Cebinelli, Guilherme Cesar ; Lopes da Fonseca, Benedito Antonio ; Silveira Leiria, Luiz Osorio ; Cunha, Larissa Dias ; Arruda, Eurico ; Nakaia, Helder, I ; Fabro, Alexandre Todorovic ; Oliveira, Rene D. R. ; Zamboni, Dario S. ; Louzada-Junior, Paulo ; Cunha, Thiago Mattar ; Farias Alves-Filho, Jose Carlos ; Cunha, Fernando Queiroz

• Document type: Journal article
• Source: Critical Care; v. 26, n. 1, p. 16-pg., 2022-07-07.

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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC