Fig. 1. The pathways of Nlrp3 inflammasome activation in response to SARS-CoV-2 infection that may lead to initiation of cytokine storm and pyroptosis in cells including HSPCs.

a It is possible that, by binding to ACE2 via the spike protein, SARS-CoV-2 directly activates the Nlrp3 inflammasome. This possibility is currently being investigated by our team. b Activation of the renin–angiotensin–aldosterone system (RAAS) leads to elevated levels of angiotensin II, which, after binding to the AT1 receptor, activates the Nlrp3 inflammasome in target cells. c Finally, the N proteins of the SARS-CoV-2 virus may activate the ComC in an MBL–MASP-2-dependent manner, and the ComC cleavage fragments (the C3a and C5a anaphylatoxins), as well as the C5b/C9 membrane attack complex (MAC), may additionally activate the Nlrp3 inflammasome in cells. (Of note, MASP-2 also activates the coagulation cascade by converting prothrombin into thrombin). Overall, activation of all three of these pathways leads to activation of caspase 1, the release of the mature IL-1β and IL-18 cytokines, the insertion of gasdermin D channels in the cell membrane, and the release of danger-associated molecular pattern molecules (DAMPs), which amplify the innate immune response and may lead to cell death by pyroptosis.