Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS-CoV-2 infection and long COVID.
COVID-19
T-helper cell
caspase
emricasan
red blood cell
Journal
Allergy
ISSN: 1398-9995
Titre abrégé: Allergy
Pays: Denmark
ID NLM: 7804028
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
21
04
2021
received:
17
02
2021
accepted:
22
04
2021
pubmed:
17
5
2021
medline:
5
1
2022
entrez:
16
5
2021
Statut:
ppublish
Résumé
COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela. Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls. Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
Sections du résumé
BACKGROUND
COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela.
AIMS
Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease.
MATERIALS & METHODS
We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls.
RESULTS
Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition.
DISCUSSION
Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed.
CONCLUSION
Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
Identifiants
pubmed: 33993490
doi: 10.1111/all.14907
pmc: PMC8222863
doi:
Substances chimiques
Caspase Inhibitors
0
CASP3 protein, human
EC 3.4.22.-
CASP7 protein, human
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Caspase 7
EC 3.4.22.-
Caspases
EC 3.4.22.-
Caspase 1
EC 3.4.22.36
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
118-129Subventions
Organisme : NHLBI NIH HHS
ID : K01 HL140271
Pays : United States
Informations de copyright
© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
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