Inflammasome activation and pyroptosis
Studies of peripheral blood and post-mortem tissues from severe COVID-19 cases reveal high levels of IL-1β and IL-6, and increased numbers of CD14+IL-1β monocytes suggesting activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome, essential for effective antiviral immune responses, is elicited by several factors associated with SARS-CoV infection including RAS disbalance, engagement of PPR, TNFR and IFNAR, mitochondrial ROS production, complement components including MAC, as well as SARS-CoV viral proteins such as ORF3a, N and E [figure 3, (55,85)]. As a consequence, NLRP3 interaction with adaptor apoptosis speck-like protein (ASC) recruits and activates procaspase-1 processing pro-IL-1β, pro-IL-18 to the activate forms [figure 3]. This drives the propyroptotic factor gasdermin D (GSDMD) formation of pores in the cell membrane, i.e. pyroptosis that facilitates the release of proinflammatory cytokines. The pores also aid the release of cellular DAMPS such as HMGB1, and viral PAMPS that further exacerbate inflammation suggesting that targeting the NLRP3 pathway might be beneficial in severe COVID-19 cases.