Fig. 6

Diagram of cellular pathways activated by SARS-CoV-2 S protein and the targets for pharmacological interference. In human monocytes and HUVEC, S protein as an isolated element activates NF-κB, promotes the release of pro-inflammatory cytokines and triggers the priming and activation of the NLRP3 inflammasome system, leading to the formation and release of mature IL-1β. This cytokine can in turn act on IL-1R, thus fueling and amplifying an auto-inflammatory loop. Moreover, S protein enhances the cellular content of factors involved in coagulation processes, including vWF, FVIII and TF. In human endothelial cells, S protein fails to over-express the protease ADAMS-13 in order to counteract the hypercoagulation capacity of vWF multimers. While these effects of S protein are mediated by TLR4 in human monocytes, the receptors involved in HUVEC remain to be elucidated. Drugs such as anakinra, TAK242 (resotorvid), MCC950, or anti-coagulant drugs could interfere with the deleterious pro-inflammatory and pro-coagulant actions of S protein