Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients
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Abstract
Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1β, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.
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In ageing patients, SARS-CoV-2 can enhance NLRP3 inflammasome activation, IL-1β and IL-18 levels, pyroptosis and DAMP release, further increasing inflammation and COVID-19 pathogenesis.
“In ageing patients, SARS-CoV-2 can potentiate NLRP3 inflammasome activation and IL-1β and IL-18 levels, pyroptosis, and the release of DAMPs (including ATP), further heightening inflammation and COVID-19 pathogenesis74,75.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [75]
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- Authors
- Rodrigues, T. S., de Sá, K. S. G., Ishimoto, A. Y., Becerra, A., Oliveira, S., Almeida, L., Gonçalves, A. V., Perucello, D. B., Andrade, W. A., Castro, R., Veras, F. P., Toller-Kawahisa, J. E., Nascimento, D. C., de Lima, M. H. F., Silva, C. M. S., Caetite, D. B., Martins, R. B., Castro, I. A., Pontelli, M. C., de Barros, F. C., do Amaral, N. B., Giannini, M. C., Bonjorno, L. P., Lopes, M. I. F., Santana, R. C., Vilar, F. C., Auxiliadora-Martins, M., Luppino-Assad, R., de Almeida, S. C. L., de Oliveira, F. R., Batah, S. S., Siyuan, L., Benatti, M. N., Cunha, T. M., Alves-Filho, J. C., Cunha, F. Q., Cunha, L. D., Frantz, F. G., Kohlsdorf, T., Fabro, A. T., Arruda, E., de Oliveira, R. D. R., Louzada-Junior, P., & Zamboni, D. S.
- Affiliations
- Universidade de São Paulo (BR)
- Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 1
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 4
- Departamento de Biologia, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 5
- Divisão de Imunologia Clinica, Emergência, Doenças Infecciosas e Unidade de Terapia Intensiva, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 7
- Divisão de Medicina Intensiva, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 8
- Departamento de Patologia e Medicina Legal, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 9
- Center of Research in Inflammatory Diseases, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil 2
- Corresponding author
- Zamboni, Dario S.
- ORCID
- Rodrigues, Tamara S.
- de Sá, Keyla S.G.
- Ishimoto, Adriene Y.
- Becerra, Amanda
- Oliveira, Samuel
- Almeida, Leticia
- Gonçalves, Augusto V.
- Perucello, Debora B.
- Andrade, Warrison A.
- Castro, Ricardo
- Veras, Flavio P.
- Toller-Kawahisa, Juliana E.
- Nascimento, Daniele C.
- de Lima, Mikhael H.F.
- Silva, Camila M.S.
- Caetite, Diego B.
- Martins, Ronaldo B.
- Castro, Italo A.
- Pontelli, Marjorie C.
- de Barros, Fabio C.
- do Amaral, Natália B.
- Giannini, Marcela C.
- Bonjorno, Letícia P.
- Lopes, Maria Isabel F.
- Santana, Rodrigo C.
- Vilar, Fernando C.
- Auxiliadora-Martins, Maria
- Luppino-Assad, Rodrigo
- de Almeida, Sergio C.L.
- de Oliveira, Fabiola R.
- Batah, Sabrina S.
- Siyuan, Li
- Benatti, Maira N.
- Cunha, Thiago M.
- Alves-Filho, José C.
- Cunha, Fernando Q.
- Cunha, Larissa D.
- Frantz, Fabiani G.
- Kohlsdorf, Tiana
- Fabro, Alexandre T.
- Arruda, Eurico
- de Oliveira, Renê D.R.
- Louzada-Junior, Paulo
- Zamboni, Dario S.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2020-11-24
- Volume
- 218
- Issue
- 3
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC7684031
- OpenAlex
- W3109926113
- Cited by
- 839
- References
- 34
- Citations by year
- 2026: 54 · 2025: 66 · 2024: 82 · 2023: 172 · 2022: 262 · 2021: 190 · 2020: 12
- FWCI
- 51.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/08216-2, 2019/11342-6, 2020/04964-8)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (304775/2016-9)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.507253/2020-00)
- Center for Research in Inflammatory Disease (2013/08216-2)
- Instituto Nacional de Ciência e Tecnologia de Vacinas
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- NLRP3 inflammasome, SARS-CoV-2, COVID-19 severity, IL-18, IL-1β, interleukin-6, lactate dehydrogenase, peripheral blood mononuclear cells, postmortem tissue, inflammatory markers, therapeutic target
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, COVID-19, SARS-CoV-2, Humans, Lung, Monocytes, Postmortem Changes, Severity of Illness Index, Comorbidity, Cytokines, Treatment Outcome, Apoptosis, Inflammasomes
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