TY - JOUR
T1 - Caspases and therapeutic potential of caspase inhibitors in moderate–severe SARS-CoV-2 infection and long COVID
AU - Plassmeyer, Matthew
AU - Alpan, Oral
AU - Corley, Michael J.
AU - Premeaux, Thomas A.
AU - Lillard, Kimberleigh
AU - Coatney, Paige
AU - Vaziri, Tina
AU - Michalsky, Suzan
AU - Pang, Alina P.S.
AU - Bukhari, Zaheer
AU - Yeung, Stephen T.
AU - Evering, Teresa H.
AU - Naughton, Gail
AU - Latterich, Martin
AU - Mudd, Philip
AU - Spada, Alfred
AU - Rindone, Nicole
AU - Loizou, Denise
AU - Ulrik Sønder, Søren
AU - Ndhlovu, Lishomwa C.
AU - Gupta, Raavi
N1 - Funding Information:
None for the study The authors wish to acknowledge all the study participants and multiple parties who have advanced the science around caspase biology. This study is dedicated in memory of those who did not survive COVID-19.
Publisher Copyright:
© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107009649&partnerID=8YFLogxK
U2 - 10.1111/all.14907
DO - 10.1111/all.14907
M3 - Article
C2 - 33993490
AN - SCOPUS:85107009649
SN - 0105-4538
VL - 77
SP - 118
EP - 129
JO - Allergy: European Journal of Allergy and Clinical Immunology
JF - Allergy: European Journal of Allergy and Clinical Immunology
IS - 1
ER -