Fig. 1: Virus-intrinsic and host-intrinsic mechanisms of inflammasome activation.

Virus intrinsic mechanisms (red arrows): severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions enter epithelial cells via angiotensin-converting enzyme 2 (ACE2) and can enter monocytes by binding to anti-spike antibodies followed by Fc receptor for IgG (FcγR)-mediated internalization. Upon translation of the viral genome, the viroporins ORF3a and E can trigger K⁺ efflux or Ca²⁺ influx to promote NLRP3 activation. Viral N protein can bind directly to NLRP3, resulting in its activation. Host-intrinsic mechanisms (blue arrows): oxidation of lung surfactant phospholipids results in oxidized phospholipids (oxPLs), which can activate caspase 4 and/or caspase 5 to promote noncanonical inflammasome activation. Complement products such as C5a can activate NLRP3 by promoting accumulation of reactive oxygen species (ROS). ATP released by dead cells binds to P2X7 receptor, which causes K⁺ efflux and NLRP3 activation. Dead cells, bacterial co-infection or damaged mitochondria can result in cytosolic double-stranded DNA (dsDNA), which activates the AIM2 inflammasome. NLRP3 and AIM2 inflammasome assembly activates caspase 1, which cleaves full-length (FL) gasdermin D (GSDMD) into amino-terminal (NT) and carboxy-terminal (CT) fragments. The GSDMD NT fragment binds to the plasma membrane, oligomerizes and inserts itself as a pore. Caspase 1 also cleaves pro-IL-1β and pro-IL-18 into their mature forms, which are released through the GSDMD pore. IL-1β can activate macrophages to secrete additional proinflammatory cytokines such as IL-6. Pyroptosis results after further membrane damage, which releases lactate dehydrogenase (LDH) and is associated with the formation of tissue factor-enriched extracellular vesicles (EVs). CRP, C-reactive protein; ERGIC, endoplasmic reticulum–Golgi intermediate compartment; TNF, tumour necrosis factor.