Inflammasome activation at the crux of severe COVID-19

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach

“…Although the majority of COVID-19 patients have mild clinical manifestations, some patients may develop acute respiratory distress or even severe acute respiratory syndrome (SARS), which may necessitate intensive care unit (ICU) admission [1, 2]. SARS may progress into multiorgan failure and death particularly in the elderly and individuals with comorbid disorders, including type 2 diabetes mellitus (T2DM), hypertension, and obesity [2].…”

“…Although the majority of COVID-19 patients have mild clinical manifestations, some patients may develop acute respiratory distress or even severe acute respiratory syndrome (SARS), which may necessitate intensive care unit (ICU) admission [1, 2]. SARS may progress into multiorgan failure and death particularly in the elderly and individuals with comorbid disorders, including type 2 diabetes mellitus (T2DM), hypertension, and obesity [2]. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is accompanied by activation of immune-inflammatory pathways and sometimes with excessive inflammatory responses, which are associated with the severity of COVID-19 symptoms [2, 3].…”

“…SARS may progress into multiorgan failure and death particularly in the elderly and individuals with comorbid disorders, including type 2 diabetes mellitus (T2DM), hypertension, and obesity [2]. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is accompanied by activation of immune-inflammatory pathways and sometimes with excessive inflammatory responses, which are associated with the severity of COVID-19 symptoms [2, 3]. Most importantly, during SARS-CoV-2 infection, the cytokine network is activated including increased levels of interleukin (IL)-1, IL-18 and tumor necrosis factor (TNF)-α in the peripheral blood [4, 5].…”

“…Most importantly, during SARS-CoV-2 infection, the cytokine network is activated including increased levels of interleukin (IL)-1, IL-18 and tumor necrosis factor (TNF)-α in the peripheral blood [4, 5]. Severe COVID-19 is not only characterized by dysregulated release of these and other pro-inflammatory cytokines but also by acute lung injury and pneumonia, which can progress into SARS, disseminated intravascular coagulation, multisystem failure, and death [2]. In COVID-19, chest computed tomography scan anomalies (CCTA) and reduced peripheral capillary oxygen saturation (SpO2) are strongly associated with immune activation and inflammation [6].…”

“…There is some evidence that SARS-CoV-2 stimulates the inflammasomes, a group of multimeric protein complexes which are responsive to pathogen-associated molecular patters (PAMPs), damage-associated molecular patterns (DAMPs) and environmental toxins [2, 7]. In COVID-19, the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection as discovered in postmortem PBMCs and tissues of patients with moderate and critical COVID-19 [7,8,9].…”