CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation

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Rodrigues, Tamara S. ; Caetano, Camila C. S. ; de Sa, Keyla S. G. ; Almeida, Leticia ; Becerra, Amanda ; Goncalves, Augusto, V ; Lopes, Leticia de Sousa ; Oliveira, Samuel ; Mascarenhas, Danielle P. A. ; Batah, Sabrina S. ; Silva, Bruna M. ; Gomes, Giovanni F. ; Castro, Ricardo ; Martins, Ronaldo B. ; Avila, Jonathan ; Frantz, Fabiani G. ; Cunha, Thiago M. ; Arruda, Eurico ; Cunha, Fernando Q. ; Nakaya, Helder ; Cunha, Larissa D. ; Fabro, Alexandre T. ; Louzada-Junior, Paulo ; de Oliveira, Rene D. R. ; Zamboni, Dario S.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Infectious Diseases; v. 227, n. 12, p. 12-pg., 2023-02-10.

Resumo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers activation of the NLRP3 inflammasome, which promotes inflammation and aggravates severe COVID-19. Here, we report that SARS-CoV-2 induces upregulation and activation of human caspase-4/CASP4 (mouse caspase-11/CASP11), and this process contributes to NLRP3 activation. In vivo infections performed in transgenic hACE2 humanized mice, deficient or sufficient for Casp11, indicate that hACE2 Casp11(-/-) mice were protected from disease development, with the increased pulmonary parenchymal area, reduced clinical score of the disease, and reduced mortality. Assessing human samples from fatal cases of COVID-19, we found that CASP4 was expressed in patient lungs and correlated with the expression of inflammasome components and inflammatory mediators, including CASP1, IL1B, IL18, and IL6. Collectively, our data establish that CASP4/11 promotes NLRP3 activation and disease pathology, revealing a possible target for therapeutic interventions for COVID-19. SARS-CoV-2 induces upregulation and activation of human caspase-4 (mouse caspase-11), a process that contributes to NLRP3 inflammasome activation and disease exacerbation in severe cases of COVID-19. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 20/04964-8 - Ativação do inflamassoma pelo SARS-CoV-2 e o papel dessa plataforma na patogênese do COVID-19: estudo prospectivo visando inibição de NLRP3 para tratamento da COVID-19
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/11342-6 - Mecanismos e consequências da ativação de receptores citoplasmáticos por patógenos intracelulares
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Temático