Published Papers, page-17

Pyroptosis.

Pyroptosis is highly proinflammatory PCD that is activated mainly in immune cells.

Pyroptosis mediated by the NOD-, LRR-, and pyrin domain–containing protein 3 (NLRP3) inflammasome requires two signals (134). Cytokines and PAMPs provide signal 1, which induces transcription of inflammasome components and IL-1β/IL-18. Various PAMPs and DAMPs then
provide signal 2, which activates the NLRP3 inflammasome. Activated caspase-1 cleaves gasdermin D, enabling it to form permeabilizing pores on the plasma membrane. Activated caspase-1 also cleaves IL-1β/IL-18 to facilitate the release of these proinflammatory cytokines (134).

Increased caspase-1 activity and significantly elevated levels of IL-1β and IL-18 are detected in
patients with severe COVID-19 and may contribute to T cell depletion and immunopathogenesis
of SARS-CoV-2 (88). Notably, fulminant hepatitis caused by MHV3 infection is ameliorated in
NLRP3 or caspase-1 knockout mice, highlighting the roles of NLRP3 and caspase-1 in MHV3
pathogenesis (44). Interestingly, NLRP3-mediated inflammation is dampened in bat cells infected
with MERS-CoV, which partially explains how bats serve as a natural reservoir for MERS-CoV
and other zoonotic viruses (3).

The E protein and ORF3a of SARS-CoV are implicated in pyroptosis induction. Acting as a
calcium channel, SARS-CoV E protein activates the NLRP3 inflammasome in VeroE6 cells (101)
and contributes to IL-1β expression and inflammatory lung damage in a mouse model (100). By
regulating potassium efflux and mitochondrial ROS production, SARS-CoV ORF3a stimulates
IL-1β secretion in lipopolysaccharide-primed macrophages (17).Mechanistically, ORF3a not only
promotes ubiquitination and activation of NF-κB/p105 to induce transcription of pro-IL-1β (signal 1) but also facilitates the assembly of the NLRP3 inflammasome (signal 2) (129).