Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

Abstract

At present, there are is no effective vaccine and only one FDA approved early-stage therapy against infection with the SARS-CoV-2 virus to prevent disease progression. The excessive inflammation and tissue damage associated with COVID-19 can lead to immediate (i.e. respiratory failure, sepsis, and ultimately, death) or long-term health problems (i.e. fatigue, dyspnea, cough, joint pain, anosmia) and the risk for these complications are higher in the elderly population, certain ethnic groups, as well as those with various co-morbid conditions. Cellular caspases play a role in the pathophysiology of a number of disorders that overlap with the list of co-morbid conditions seen in severe COVID-19. In this study, we assessed transcriptional states of caspases in immune cells from COVID-19 patients and profiled intra-cellular caspases in immune cells and red blood cells derived from a spectrum of COVID-19 patients hospitalized with acute disease or convalescent. Gene expression levels of select caspases were increased in in vitro SARS-CoV-2 infection models and single cell RNA-Seq data of peripheral blood from COVID-19 patients showed a distinct pattern of caspase expression in T cell, neutrophils, and dendritic cells. Flow cytometric evaluation of CD4 T cells showed up-regulation of caspase-1 in hospitalized COVID-19 patients compared to unexposed controls, with the exception of a subset of patients with asthma and chronic rhinosinusitis (CRS). Convalescent COVID-19 patients with lingering symptoms (long haulers) showed persistent up-regulation of caspase-1 in CD4 T cells that was attenuated ex vivo following co-culture with a select pan-caspase inhibitor. Further, we observed elevated caspase 3 levels in red blood cells from COVID-19 patients compared to controls that were responsive to caspase inhibition. Taken together, our results expose an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate, reduce, or prevent severe COVID-19 outcomes.

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“…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 (Plassmeyer et al 2020). 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 (Donia & Bokhari, 2021, though sometimes drugs with unbalanced risk:benefit ratio were suggested (Fakhri et al 2021).…”

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“…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].…”