Inflammasome activation and pyroptosis in lymphopenic liver patients with COVID-19

Kroemer, Alexander; Khan, Khalid; Plassmeyer, Matthew; Alpan, Oral; Haseeb, M. A.; Gupta, Raavi; Fishbein, Thomas M.

doi:10.1016/j.jhep.2020.06.034

Cited by 28 publications

(44 citation statements)

References 10 publications

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“…Several clinical studies showed that increased inflammasome activity leads to immune dysregulation and ultimately severe disease for COVID-19 patients (11)(12)(13). A recent study directly demonstrates that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection (14).…”

Section: Introductionmentioning

confidence: 99%

Key Components of Inflammasome and Pyroptosis Pathways Are Deficient in Canines and Felines, Possibly Affecting Their Response to SARS-CoV-2 Infection

Cui

Zhang

2021

Front. Immunol.

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SARS-CoV-2 causes the ongoing COVID-19 pandemic. Natural SARS-COV-2 infection has been detected in dogs, cats and tigers. However, the symptoms in canines and felines were mild. The underlying mechanisms are unknown. Excessive activation of inflammasome pathways can trigger cytokine storm and severe damage to host. In current study, we performed a comparative genomics study of key components of inflammasome and pyroptosis pathways in dogs, cats and tigers. Cats and tigers do not have AIM2 and NLRP1. Dogs do not contain AIM2, and encode a short form of NLRC4. The activation sites in GSDMB were absent in dogs, cats and tigers, while GSDME activation sites in cats and tigers were abolished. We propose that deficiencies of inflammasome and pyroptosis pathways might provide an evolutionary advantage against SARS-CoV-2 by reducing cytokine storm-induced host damage. Our findings will shed important lights on the mild symptoms in canines and felines infected with SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

Key Components of Inflammasome and Pyroptosis Pathways Are Deficient in Canines and Felines, Possibly Affecting Their Response to SARS-CoV-2 Infection

Cui

Zhang

2021

Front. Immunol.

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“…Preventing the pyroptotic lymphocyte death by using caspase inhibitors may lead to better success rather than inhibition of the inflammatory response from the cell death itself. The failure of cytokine targeted therapies could be due to that adaptive immune dysfunction due to AVID weighing more heavily than an inflammatory response in disease progression (18).…”

Section: Discussionmentioning

confidence: 99%

“…Inflammasome activation in peripheral immune cells and tissues was recently observed in COVID-19 patients and the level of inflammasome-derived products, including active caspase-1, associated with disease severity and poor outcomes (17). We recently reported that caspase-1 expression in lymphocytes and serum IL-18 levels are increased in liver transplant patients acutely ill with SARS-CoV-2 infection suggesting pyroptosis mechanisms may play role in severe COVID-19 (18). A recent study showed that SARS-CoV-2 infection of rhesus macaques led to an upregulation of caspase-1 molecular signature in peripheral blood cells as early as day 2 post-inoculation (19).…”

Section: Introductionmentioning

confidence: 99%

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

Plassmeyer¹,

Alpan²,

Corley

et al. 2021

Preprint

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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.

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“…The end result is likely a self-damaging cell death and subsequent cytokine storm that further fuels the inflammation created by the viral infection, resulting in AVID. The failure of cytokine targeted therapies could be due to that adaptive immune dysfunction weighs more heavily than an inflammatory response in disease progression (15). This connection between caspase-1 and COVID-19 has significant therapeutic implications since preventing the pyroptotic lymphocyte death rather than inhibition of the inflammatory response may be a more efficacious therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that caspase-1 expression in lymphocytes and serum IL-18 levels are increased in liver transplant patients acutely ill with SARS-CoV-2 infection, along with non-liver transplant controls, suggesting pyroptosis mechanisms may play role in severe COVID-19 (15). A recent study showed that SARS-CoV-2 infection of rhesus macaques led to an upregulation of caspase-1 molecular signature in peripheral blood cells as early as day 2 post-inoculation (16).…”

Section: Introductionmentioning

confidence: 99%

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

Plassmeyer¹,

Alpan²,

Corley

et al. 2020

Preprint

Self Cite

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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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Inflammasome activation and pyroptosis in lymphopenic liver patients with COVID-19

Cited by 28 publications

References 10 publications

Key Components of Inflammasome and Pyroptosis Pathways Are Deficient in Canines and Felines, Possibly Affecting Their Response to SARS-CoV-2 Infection

Key Components of Inflammasome and Pyroptosis Pathways Are Deficient in Canines and Felines, Possibly Affecting Their Response to SARS-CoV-2 Infection

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

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

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