THE CYTOKINE STORM
SARS-CoV-2 binds to the Angiotensin-converting enzyme 2 (ACE2) receptor and enters the host cell (1). During infection, the innate and adaptive immune systems work together to inactivate the virus. Since leukocytes and neutrophils are present in higher concentrations in COVID-19 individuals, these immune cells may result in the cytokine storm (10). After viral entry, the virus induces pyroptosis and cell death. The dead cells recruit macrophages to the site of injury that phago-cytose them. The phagocytes then express damage-associated molecular patterns (DAMPs), which bind to the toll-like receptors (TLR) and induce nuclear factor kappa B (NF-κb) signalling by means of the MyD88 pathway. NF-κb enters the nucleus and catalyzes the transcription of pro-IL-1β and pro-caspase-1. When additional signals are detected, the pro-IL-1β and procaspase 1 are cleaved into IL-1β and caspase 1 (12). The activated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) recruits the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-cas-pase-1 to form the NLRP3 inflammasome (13). In addition, the phagocytosis releases ATP, which binds to the P2X purino-ceptor 7 (P2RX7) and activates the inflammasome (14). The increased calcium levels caused by the viral proteins results in lysosomal damage, thereby releasing cathepsins that activate the inflammasome (15). Further, the binding of SARS-CoV-2 to the ACE2 reduces the available ACE2 receptors on the cell surface. This increases the levels of Angiotensin II (AngII) in the extracellular space, because ACE2 converts AngI and AngII into Ang 1-9 and Ang1-7, respectively. AngII increases the levels of TNF-α and IL-6 in the cell that upregulates NF-κb, activating the inflammasome (12). The continuous activation of the inflammasome results in a cytokine storm, which recruits more immune cells, necrosis, and cell death. This inflamma-some pathway further causes tissue injury in various organs (Fig. 1).