Complement control for COVID-19

Abstract

Excessive complement activation contributes to lung disease and adverse patient outcomes in COVID-19 (see the related Research Articles by Yan et al and Ma et al).

Fig. 1. Current concepts of complement activation and potential therapeutic interventions in severe COVID-19.

SARS-CoV-2 infection of alveolar epithelial cells (type II and type I) and subsequent interferon-dependent JAK1/2-STAT1–induced expression of C3 and factor B culminates in nontraditional intracellular processing of complement proteins. In the extracellular spaces, SARS-CoV-2 activates complement via the MBL/ficolin pathway, which senses glycosylated S and N proteins. The C3 tick-over of the alternative pathway is accelerated by a lack of complement inhibitors (CD46, CD55, and CD59) on infected host cells and virions. The classical pathway is activated by antibodies against viral antigens and COVID-19–associated autoantibodies. All complement activation mechanisms converge on the C3/C5 hub to form the MAC (C5b-C9) and generate anaphylatoxins (C3a and C5a). These effectors recruit myeloid cells and cause endothelial activation, endothelial injury, coagulopathy, and hyperinflammation. The figure shows the molecular targets of several complement-inhibiting drugs proposed as COVID-19 treatments: Eculizumab and ravulizumab block C5 conversion, AMY-101 and pegcetacoplan antagonize C3 activation, the IFX-1 monoclonal antibody inhibits C5a, and avdoralimab blocks the C5aR1 receptor. vWF, von Willebrand factor; Ang2, angiopoietin-2; C3aR, C3a receptor; C5aR1, C5a receptor 1; C5aR2, C5a receptor 2; MASP1/2, mannan-binding lectin serine proteases 1 and 2; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease, serine 2.