Allergy · 2021
Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS-CoV-2 infection and long COVID.
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Plassmeyer Matthew, Alpan Oral, Corley Michael J, Premeaux Thomas A, Lillard Kimberleigh, Coatney Paige, Vaziri Tina, Michalsky Suzan, Pang Alina P S, Bukhari Zaheer, Yeung Stephen T, Evering Teresa H, Naughton Gail, Latterich Martin, Mudd Philip, Spada Alfred, Rindone Nicole, Loizou Denise, Ulrik Sønder Søren, Ndhlovu Lishomwa C, Gupta Raavi
Аннотация
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.
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.