Figure 2.

Complement activation during SARS-CoV-2-related ARDS. SARS-CoV-2 infection of alveolar epithelial cells (type II and type I) and endothelial cells may trigger complement activation via the three pathways of complement activation. The binding of the SARS-CoV-2 nucleocapsid protein to MASP-2 may activate the lectin pathway of complement activation. Activation of the alternative pathway could be facilitated by the lack of complement inhibitors (CD46, CD55, and CD59) on infected alveolar cells and virions. IgM to SARS-CoV-2 may efficiently activate the classical pathway. The three complement activation pathways converge to generate the C3a and C5a anaphylatoxins and the Membrane Attack Complex (C5b-C9) (MAC). C3a and C5a are potent chemoattractants and inflammatory mediators that recruit and activate neutrophils and monocytes/macrophages. Deposition of MAC on the membranes of alveolar epithelial cells and endothelial cells leads to cell lysis. Complement overactivation may promote hypercoagulability and thrombosis via several mechanisms, including activation and injury of endothelial cells, platelet aggregation and platelet prothrombinase activation, and inhibition of fibrinolysis. Also, MASP-2, in addition to trigger complement activation, may cleave prothrombin to form activated thrombin. Created with BioRender.com.