Inflammasome formation in the lungs of patients with fatal COVID-19
Open accessAbstract
Objective The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS). Methods Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1. Results Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064). Conclusions These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.
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SARS-CoV-2 infection strongly activates complement and other innate immune pathways such as TLR4 and the inflammasome, leading to increased IL-1β and IL-18 levels.
“SARS-CoV-2 infection has been documented to strongly activate complement and to activate other innate immune pathways such as TLR4 and the inflammasome, which leads to increased IL-1 β and IL-18 levels. 137-142”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [140]
The Results (page unavailable) show substantially more inflammasome aggregates in lung samples from four patients with fatal COVID-19 than in controls. The Discussion links the inflammasome to cytokine release and identifies IL-1β and IL-18 as derived cytokines, but does not establish increased levels of either; the paper also does not address complement or TLR4 activation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOther key innate cytokines elevated during COVID-19 include TNFα and IL-6, which is increased by IL-1β.
“Other key innate cytokines that are elevated during COVID-19 include TNF α and IL-6, which is increased by IL-1 β . 137-142”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [140]
The Introduction (page unavailable) discusses elevated pro-inflammatory mediators in COVID-19, and the Discussion (page unavailable) names IL-1β as a cytokine associated with inflammasome activation. Neither section identifies TNFα or IL-6 as elevated, or says that IL-1β increases IL-6. Searches for TNF, IL-6, and that proposed relationship found no supporting passage in our copy. (LLM, conf=0.73)
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- Authors
- Toldo, S., Bussani, R., Nuzzi, V., Bonaventura, A., Mauro, A. G., Cannatà, A., Pillappa, R., Sinagra, G., Nana-Sinkam, P., Sime, P., & Abbate, A.
- Affiliations
- Virginia Commonwealth University (US)
- University of Trieste (IT)
- Corresponding author
- Toldo, Stefano
- ORCID
- Venue
- Inflammation Research
- Published
- 2020-10-20
- Volume
- 70
- Issue
- 1
- Pages
- 7-10
- ISSN
- 1023-3830 (ISSN-L)
- 1420-908X
- PMC
- PMC7572246
- OpenAlex
- W3092938204
- Cited by
- 132
- References
- 15
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 16 · 2023: 23 · 2022: 40 · 2021: 42 · 2020: 2
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Inflammation Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- United States of America National Institute of Health NHLBI (R01HL150115)
- 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, COVID-19 pandemic, SARS-CoV-2, acute respiratory distress syndrome, lung injury, ASC, caspase-1, cytokine release syndrome, macrophages
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Cytokine Release Syndrome, COVID-19, Adult, Aged, Autopsy, Female, Heart Arrest, Humans, Leukocytes, Lung, Male, Middle Aged, Pneumonia, Viral, Respiratory Distress Syndrome, Caspase 1, CARD Signaling Adaptor Proteins, Inflammasomes
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