The state of complement in COVID-19

Abstract

Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.

Fig. 1. Complement as driver of and therapeutic target in COVID-19.

Schematic summary of the currently known contributions of complement to COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggers direct or indirect activation of extracellular and/or intracellular complement pathways. SARS-CoV-2 envelope proteins activate the lectin pathway through binding to mannose-binding lectin (MBL) or the classical pathway through SARS-CoV-2-specific antibodies and C1q. Competition of SARS-CoV-2 with C3b-regulatory factor H (FH) for binding to heparan sulfate removes the inhibitory effects of factor H on C3, sustaining activation of the alternative pathway. Infection-induced type I interferon receptor (IFNAR) signalling through the Janus kinase (JAK)–signalling transducer and activator of transcription 1 (STAT1) pathway in type II pneumocytes induces production of intracellular complement factor B (FB) and C3, which seed an intracellular C3 convertase and cleavage-mediated activation of intracellular C3. Type II pneumocyte-generated C3 activation fragments engage cognate receptors (C3a–C3aR and C3b–CD46) on immune cells in the vicinity and induce their (hyper)activation. SARS-CoV-2-induced complement activation in the capillaries increases C5a generation. C5a potentiates activation of leukocytes and neutrophils, their adhesion to endothelial cells, their production of proinflammatory cytokines and/or the formation of local neutrophil extracellular traps (NETs). SARS-CoV-2-primed endothelial cells upregulate C5a receptor 1 (C5aR1) expression and become vulnerable to pathological C5a activation and insertion of the membrane attack complex (MAC), which cumulatively cause endothelial cell death and loss of thromboresistance. Simultaneously, complement induces platelet activation (mostly via action of the MAC) and activation of the coagulation cascade (mostly via action of MBL-associated serine protease 1 (MASP1) or MASP2), supporting detrimental thrombus formation. Current pharmacological interventions with specific complement targets are depicted. These include antivirals and JAK or STAT inhibitors, which reduce infection-induced extracellular and intracellular complement activation, and drugs that block MASP1 or MASP2 activity and classical pathway and C5 activation. Several therapeutics aim at inhibiting C3 and C5 activation fragments, and one inhibitory antibody blocks C5aR1 stimulation. ACE2, angiotensin-converting enzyme 2; IRF, interferon regulatory factor; RELA, nuclear factor-κB p65 subunit.