학술논문
Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology
Document Type
article
Author
Silva, Camila Meirelles S; Wanderley, Carlos Wagner S; Veras, Flavio Protasio; Gonçalves, Augusto Velozo; Lima, Mikhael Haruo Fernandes; Toller-Kawahisa, Juliana Escher; Gomes, Giovanni Freitas; Nascimento, Daniele Carvalho; Monteiro, Valter V Silva; Paiva, Isadora Marques; Almeida, Cícero José Luíz Ramos; Caetité, Diego Brito; Silva, Juliana Costa; Lopes, Maria Isabel Fernandes; Bonjorno, Letícia Pastorelli; Giannini, Marcela Cavichioli; Amaral, Natalia Brasil; Benatti, Maíra Nilson; Santana, Rodrigo Carvalho; Damasceno, Luis Eduardo Alves; Silva, Bruna Manuella Souza; Schneider, Ayda Henriques; Castro, Icaro Maia Santos; Silva, Juan Carlo Santos; Vasconcelos, Amanda Pereira; Gonçalves, Tiago Tomazini; Batah, Sabrina Setembre; Rodrigues, Tamara Silva; Costa, Victor Ferreira; Pontelli, Marjorie Cornejo; Martins, Ronaldo B; Martins, Timna Varela; Espósito, Danillo Lucas Alves; Cebinelli, Guilherme Cesar Martelossi; da Fonseca, Benedito Antônio Lopes; Leiria, Luiz Osório Silveira; Cunha, Larissa Dias; Arruda, Eurico; Nakaia, Helder I; Fabro, Alexandre Todorovic; Oliveira, Rene DR; Zamboni, Dario S; Louzada-Junior, Paulo; Cunha, Thiago Mattar; Alves-Filho, José Carlos Farias; Cunha, Fernando Queiroz
Source
Critical Care. 26(1)
Subject
Language
Abstract
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.