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

Autor:	Silva CMS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Wanderley CWS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Veras FP; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Gonçalves AV; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Lima MHF; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Toller-Kawahisa JE; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Gomes GF; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Nascimento DC; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Monteiro VVS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Paiva IM; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Almeida CJLR; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Caetité DB; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Silva JC; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Lopes MIF; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Bonjorno LP; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Giannini MC; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Amaral NB; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Benatti MN; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Santana RC; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Damasceno LEA; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Silva BMS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Schneider AH; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Castro IMS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Silva JCS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Vasconcelos AP; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Gonçalves TT; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil., Batah SS; Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Rodrigues TS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Costa VF; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Pontelli MC; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.; Virology Research Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Martins RB; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.; Virology Research Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Martins TV; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Espósito DLA; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Cebinelli GCM; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., da Fonseca BAL; Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Leiria LOS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Cunha LD; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Arruda E; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.; Virology Research Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Nakaia HI; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Hospital Israelita Albert Einstein, São Paulo, Brazil., Fabro AT; Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Oliveira RDR; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Zamboni DS; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Louzada-Junior P; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Cunha TM; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Alves-Filho JCF; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Cunha FQ; Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil. fdqcunha@fmrp.usp.br.; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. fdqcunha@fmrp.usp.br.
Jazyk:	angličtina
Zdroj:	Critical care (London, England) [Crit Care] 2022 Jul 07; Vol. 26 (1), pp. 206. Date of Electronic Publication: 2022 Jul 07.
DOI:	10.1186/s13054-022-04062-5
Abstrakt:	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. (© 2022. The Author(s).)
Databáze:	MEDLINE
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