Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection

Abstract

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8– and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)–mediated inflammatory cell death after coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered due to the absence of GSDMD. Altogether our findings show that inflammatory cell death is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.

COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses

“…However, the PD-L1-PD-1 axis may also lead to enhanced T cell apoptosis, further supported by a significant increase in frequencies of T cells with active caspases. In addition, there is in vitro evidence that caspase-8-dependent cell death may be induced by a murine coronavirus as well as SARS-CoV-2 ( Li et al., 2020 ; Zheng et al., 2020 ). In contrast to PD-1, Tim-3 + T cell frequencies were reduced in ACs, while we observed increased amounts of sTim-3 in plasma of ACs.…”

Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx–dependent pyroptosis in intestinal epithelial cells

“…15% of EPEC-1-infected cells sill exhibiting PI uptake compared with EPEC-0-infected cells ( Fig 2D). As necroptosis can be activated during pyroptosis inhibition [48], we investigated if the residual cell death is due to necroptosis. For this, we used necrostatin-1 (Nec1) to inhibit RIPK1, necrosulfonamide (NSA) to inhibit MLKL and siRNA to silence RIPK3.…”

G6PD deficiency, redox homeostasis, and viral infections: implications for SARS-CoV-2 (COVID-19)

“…The inflammasome is part of the innate immune system that regulates effector cells during inflammation [104][105][106][107]. Inflammasomes are cytosolic protein complexes consisting of multiple oligomeric molecules that detect cell-damaging agents and pathogenic factors by recognizing danger-associated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMP), respectively [104].…”

“…Activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is triggered by viral replication and leads to the destruction of viruses [105]. The murine coronavirus mouse hepatitis virus (MHV) activates NLRP3 inflammasomes and induces proinflammatory programmed cell death by panoptosis (pyroptosis, apoptosis, and necroptosis) [106,107]. The deleterious effects on the host due to inflammasome impairment indicate that balanced regulation of inflammasomes is crucial for the immune response and antiviral defense.…”