CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation
Tamara Silva Rodrigues, Camila Carla da Silva Caetano, Keyla Santos Guedes de Sá, Letícia de Almeida, Amanda Becerra, Augusto V. Gonçalves, Leticia de Sousa Lopes, Samuel Oliveira, Danielle P. A. Mascarenhas, Sabrina Setembre Batah, Bruna M. Silva, Giovanni Freitas Gomes, Ricardo Cardoso Castro, Ronaldo B. Martins, Jonathan Avila, Fabiani Gai Frantz, Thiago M. Cunha, Eurico Arruda, Fernando Q. Cunha, Helder I. Nakaya, Larissa D. Cunha, Alexandre Todorovic Fabro, Paulo Louzada‐Júnior, Renê Donizeti Ribeiro de Oliveira, Dario S. Zamboni
Abstract
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.