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CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation
Tamara S Rodrigues1, Camila C S Caetano1, Keyla S G de Sá1
1Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
The Journal of Infectious Diseases
|February 10, 2023
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection activates caspase-4/11, promoting inflammation and severe COVID-19. Targeting caspase-4/11 may offer new therapeutic strategies for COVID-19 patients.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is linked to severe COVID-19 pathogenesis.
- The NLRP3 inflammasome plays a critical role in mediating inflammatory responses during viral infections.
Purpose of the Study:
- To investigate the role of caspase-4/11 in SARS-CoV-2-induced inflammation and COVID-19 severity.
- To explore caspase-4/11 as a potential therapeutic target for COVID-19.
Main Methods:
- Infection of transgenic human ACE2 (hACE2) mice with varying Caspase-11 (Casp11) expression.
- Analysis of lung tissue and inflammatory markers in human COVID-19 patient samples.
- Assessment of NLRP3 inflammasome activation and its correlation with caspase-4/11.
Main Results:
- SARS-CoV-2 infection upregulates and activates human caspase-4 (CASP4) and mouse caspase-11 (CASP11), contributing to NLRP3 inflammasome activation.
- Mice deficient in Casp11 showed protection against severe COVID-19, with reduced disease severity and mortality.
- CASP4 expression in lungs of fatal COVID-19 cases correlated with inflammasome components (CASP1, IL1B, IL18, IL6).
Conclusions:
- Caspase-4/11 activation is a key mechanism in SARS-CoV-2-induced inflammation and COVID-19 pathology.
- Targeting the CASP4/11-NLRP3 inflammasome pathway presents a promising therapeutic avenue for managing severe COVID-19.
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