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Caspases in COVID-19 disease and sequela and the therapeutic potential of caspase inhibitors
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  • Matthew Plassmeyer,
  • Oral Alpan,
  • Michael Corley,
  • Thomas Premeaux,
  • Kimberleigh Lillard,
  • Paige Coatney,
  • Tina Vaziri,
  • Suzan Michalsky,
  • Alina Pang,
  • Zaheer Bukhari,
  • Stephen Yeung,
  • Teresa Evering,
  • Gail Naughton,
  • Martin Latterich,
  • Philip Mudd,
  • Alfred Spada,
  • Nicole Rindone,
  • Denise Loizou,
  • Soren Ulrik Sonder,
  • Lishomwa Ndhlovu,
  • Raavi Gupta
Matthew Plassmeyer
Amerimmune LLC
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Oral Alpan
Amerimmune
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Michael Corley
Weill Cornell Medicine
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Thomas Premeaux
Weill Cornell Medicine
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Kimberleigh Lillard
Amerimmune
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Paige Coatney
Amerimmune
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Tina Vaziri
Amerimmune
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Suzan Michalsky
Amerimmune
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Alina Pang
Weill Cornell Medicine
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Zaheer Bukhari
SUNY Downstate Medical Center
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Stephen Yeung
Weill Cornell Medicine
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Teresa Evering
Weill Cornell Medicine
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Gail Naughton
Histogen
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Martin Latterich
Histogen
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Philip Mudd
Washington University in St Louis Department of Medicine
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Alfred Spada
Histogen
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Nicole Rindone
Amerimmune
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Denise Loizou
Amerimmune LLC
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Soren Ulrik Sonder
Amerimmune LLC
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Lishomwa Ndhlovu
Weill Cornell Medical College
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Raavi Gupta
SUNY Downstate Medical Center
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Abstract

COVID-19 can present with lymphopenia and extraordinary complex multi-organ 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 subjects presenting with various co-morbid 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 to controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared to unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed up-regulated caspase-1 activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7 levels in red blood cells from COVID-19 patients compared to 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.

Peer review status:ACCEPTED

17 Feb 2021Submitted to Allergy
18 Feb 2021Submission Checks Completed
18 Feb 2021Assigned to Editor
18 Feb 2021Reviewer(s) Assigned
10 Mar 2021Review(s) Completed, Editorial Evaluation Pending
10 Mar 2021Editorial Decision: Revise Minor
06 Apr 20211st Revision Received
08 Apr 2021Submission Checks Completed
08 Apr 2021Assigned to Editor
10 Apr 2021Reviewer(s) Assigned
14 Apr 2021Review(s) Completed, Editorial Evaluation Pending
14 Apr 2021Editorial Decision: Revise Minor
20 Apr 20212nd Revision Received
22 Apr 2021Submission Checks Completed
22 Apr 2021Assigned to Editor
22 Apr 2021Editorial Decision: Accept