Caspases in COVID-19 disease and sequela and the therapeutic potential of caspase inhibitors
Year: 2021
Type: preprint
Study design: Observational Study
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.
Authors: 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
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W3133229384