Figure 3.

Activation of inflammasome by CoV, leading to hyperinflammation: The viroporins, ORF3a, and E can trigger K⁺ efflux or Ca²⁺ influx to induce NLRP3 activation. Moreover, the N protein can bind directly to NLRP3, inducing its activation. Additionally, mitochondrial damage can result in the production of dsDNA, which activates the AIM2 inflammasome. NLRP3 and AIM2 inflammasomes activate caspase 1, which cleaves GSDMD into amino-terminal and carboxy-terminal fragments. The GSDMD amino-terminal fragment targets and inserts itself into cellular membrane lipids, forming pores and rendering the membranes permeable. Caspase 1 cleaves pro-IL-1β into mature IL-1β, which is released through the GSDMD pore. IL-1β can stimulate monocytes to secrete additional proinflammatory cytokines such as IL-6, IL-8, and TNFα, which further upregulate inflammation by recruiting lymphocytes such as neutrophils.