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

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

Authors :
Silva, Camila Meirelles S
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
Silva, Camila Meirelles S
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; vol 26, iss 1
Publication Year :
2022

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.

Details

Database :
OAIster
Journal :
Critical Care; vol 26, iss 1
Notes :
application/pdf, Critical Care vol 26, iss 1
Publication Type :
Electronic Resource
Accession number :
edsoai.on1401037538
Document Type :
Electronic Resource