Caspases in COVID-19 disease and sequela and the therapeutic potential of caspase inhibitors

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.

Pharmacogenomics deliberations of 2-deoxy-d-glucose in the treatment of COVID-19 disease: an in silico approach

“…Interestingly, the assessment also indicated susceptible gene loci for SARS-CoV infections. The pathway assessment among 2-DG interacting genes also highlighted apoptosis-related signaling mediated by the caspase family of proteins which may modify the metabolism of cells and enhance the rate of cell death (Gioti et al 2021 ) and its potential role in viral infection inhibition (Plassmeyer et al 2021 ). Cell death due to 2-DG in various tumor cells has been reported and could be mediated by ER stress/autophagy in HCT116 colon cancer cells or through Cytochrome C-Caspase 3-PARP axis in certain other cells (Maximchik et al 2018 ).…”

The potential crucial role of COX-1 inhibition and/or Aspirin triggered lipoxins and resolvins in amelioration of COVID-19 mortality

“…Moreover, uncontrolled caspase response in COVID-19 was suggested to share the immune pathological processes as well as in the inflammatory microvascular thrombi found in multiple organs leading to severe outcomes. Interestingly, caspase-1 in CD4+ T cells was shown to be upregulated in hospitalized COVID-19 patients and caspase-3 levels were reported to be significantly upregulated, compared to controls, in circulating red blood cells from COVID-19 patients as well as in tissue macrophages in postmortem analysis and were also demonstrated to be suppressed ex vivo by a pan caspase inhibitor [16]. Thus, unsurprisingly, suppression of apoptosis was suggested to prevent viral pathogenesis in some diseases including SARS and targeting virus-induced apoptosis was implied as a promising strategy in COVID-19 management [17].…”