Critical Care (Jul 2022)
Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology
- Camila Meirelles S. Silva,
- Carlos Wagner S. Wanderley,
- Flavio Protasio Veras,
- Augusto Velozo Gonçalves,
- Mikhael Haruo Fernandes Lima,
- Juliana Escher Toller-Kawahisa,
- Giovanni Freitas Gomes,
- Daniele Carvalho Nascimento,
- Valter V. Silva Monteiro,
- Isadora Marques Paiva,
- Cícero José Luíz Ramos Almeida,
- Diego Brito Caetité,
- Juliana Costa Silva,
- Maria Isabel Fernandes Lopes,
- Letícia Pastorelli Bonjorno,
- Marcela Cavichioli Giannini,
- Natalia Brasil Amaral,
- Maíra Nilson Benatti,
- Rodrigo Carvalho Santana,
- Luis Eduardo Alves Damasceno,
- Bruna Manuella Souza Silva,
- Ayda Henriques Schneider,
- Icaro Maia Santos Castro,
- Juan Carlo Santos Silva,
- Amanda Pereira Vasconcelos,
- Tiago Tomazini Gonçalves,
- Sabrina Setembre Batah,
- Tamara Silva Rodrigues,
- Victor Ferreira Costa,
- Marjorie Cornejo Pontelli,
- Ronaldo B. Martins,
- Timna Varela Martins,
- Danillo Lucas Alves Espósito,
- Guilherme Cesar Martelossi Cebinelli,
- Benedito Antônio Lopes da Fonseca,
- Luiz Osório Silveira Leiria,
- Larissa Dias Cunha,
- Eurico Arruda,
- Helder I. Nakaia,
- Alexandre Todorovic Fabro,
- Rene D. R. Oliveira,
- Dario S. Zamboni,
- Paulo Louzada-Junior,
- Thiago Mattar Cunha,
- José Carlos Farias Alves-Filho,
- Fernando Queiroz Cunha
Affiliations
- Camila Meirelles S. Silva
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Carlos Wagner S. Wanderley
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Flavio Protasio Veras
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Augusto Velozo Gonçalves
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Mikhael Haruo Fernandes Lima
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Juliana Escher Toller-Kawahisa
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Giovanni Freitas Gomes
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Daniele Carvalho Nascimento
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Valter V. Silva Monteiro
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Isadora Marques Paiva
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Cícero José Luíz Ramos Almeida
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Diego Brito Caetité
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Juliana Costa Silva
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Maria Isabel Fernandes Lopes
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Letícia Pastorelli Bonjorno
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Marcela Cavichioli Giannini
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Natalia Brasil Amaral
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Maíra Nilson Benatti
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Rodrigo Carvalho Santana
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Luis Eduardo Alves Damasceno
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Bruna Manuella Souza Silva
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Ayda Henriques Schneider
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Icaro Maia Santos Castro
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Juan Carlo Santos Silva
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Amanda Pereira Vasconcelos
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Tiago Tomazini Gonçalves
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Sabrina Setembre Batah
- Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo
- Tamara Silva Rodrigues
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Victor Ferreira Costa
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Marjorie Cornejo Pontelli
- Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo
- Ronaldo B. Martins
- Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo
- Timna Varela Martins
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Danillo Lucas Alves Espósito
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo
- Guilherme Cesar Martelossi Cebinelli
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Benedito Antônio Lopes da Fonseca
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo
- Luiz Osório Silveira Leiria
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Larissa Dias Cunha
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Eurico Arruda
- Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo
- Helder I. Nakaia
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Alexandre Todorovic Fabro
- Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo
- Rene D. R. Oliveira
- Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo
- Dario S. Zamboni
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Paulo Louzada-Junior
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Thiago Mattar Cunha
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- José Carlos Farias Alves-Filho
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- Fernando Queiroz Cunha
- Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo
- DOI
- https://doi.org/10.1186/s13054-022-04062-5
- Journal volume & issue
-
Vol. 26,
no. 1
pp. 1 – 16
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.
Keywords
