Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients

Abstract

Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1β, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

“…Moreover, the extent of systemic inflammation is further modified by adipokines, hepatokines, myokines, lipokines, branched-chain amino acids, and microbial metabolites, which may circulate at abnormal levels in some people with T2D or obesity. Collectively, these acquired abnormalities broadly impair cellular immune function, likely contributing to enhanced activation of the NLRP3 inflammasome, and a greater susceptibility to infection in vulnerable individuals ( Rodrigues et al., 2021 ). There is considerable interest in whether the expression of viral entry factors essential for SARS-CoV-2 infectivity is enhanced in one or more tissues in people with T2D or obesity ( Figure 1 ); however, the available data are inconclusive ( Drucker, 2020 ).…”

COVID-19 stokes inflammasomes

“…A number of studies, particularly those in rodents, have suggested that activation of the NLRP3 inflammasome is important in different sepsis models (Danielski et al, 2020), and there has been much speculation that NLRP3 would be linked to the pathogenesis of COVID-19. The Zamboni paper (Rodrigues et al, 2020) provides nice evidence to support this hypothesis (see figure) in SARS-CoV-2-infected patients; however, it also suggests a role for other inflammasomes in the pathogenesis of this disease. This suggests that inhibition of NLRP3 alone may have limited usefulness in COVID-19 sepsis, although its importance in other human septic syndromes remains to be determined.…”

“…In this issue of JEM, Rodrigues et al (2020) show that activation of inflammasomes by SARS-CoV-2 infection is linked with COVID-19 disease severity in patients, potentially providing new therapeutic avenues for this intractable condition. Inflammasomes are macromolecular inflammatory signaling complexes that may be canonical (composed of a receptor, such as a nucleotide oligomerization domain leucine rich repeat receptor [NLR] or AIM-2 like receptor; an adaptor [ASC]; and an effector [caspase 1]) or noncanonical (composed of caspase 4 or 5 in humans or caspase 11 in mice; Broz and Dixit, 2016).…”

“…Application of machine learning to the analysis of the large datasets generated from different cohorts of septic patients (Giannini et al, 2019), for example, from those with COVID-19, should help to stratify different patient groups to select the most appropriate therapeutic strategies. Rodrigues et al (2020) have linked inflammasome activity with COVID-19 disease severity, which potentially provides an important biomarker to assist in patient stratification. Taking out a single cytokine or signaling pathway is unlikely to be successful in treating sepsis because of functional redundancies and the potential for destabilizing the various immunological balances particularly between inflammation, immunosuppression, and anti-inflammatory pathways.…”

Structure, Activation and Regulation of NLRP3 and AIM2 Inflammasomes

“…An upsurge of IL-1β, IL-18, and LDH (Lactate dehydrogenase) has been reported in sera of COVID-19 patients, which hints the involvement of the inflammasome network [ 107 , 108 , 109 ]. Similarly, a recent study conducted on COVID-19 patients reveals the activation of the NLRP3 inflammasome [ 110 ]. In this study, microscopic analysis in combination with luminescent assays show the formation of NLRP3 and ASC puncta, caspase-1 activation, and IL-1β secretion in PBMCs (Peripheral blood mononuclear cells) of COVID-19 patients during the disease and in postmortem lung tissues [ 110 ].…”