Complement control for COVID-19

 Markus Bosmann1,2,3,4,*

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Science Immunology  25 May 2021:
Vol. 6, Issue 59, eabj1014
DOI: 10.1126/sciimmunol.abj1014

PDF: https://immunology.sciencemag.org/content/6/59/eabj1014/tab-pdf

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.).

The complement system is an integral part of innate immune defense. It consists of about 50 proteins in plasma, on cell surfaces and inside host cells. The traditional view is that complement proteins guard the local extracellular spaces and systemic bloodstream against invading pathogens. Loss-of-function mutations resulting in terminal complement pathway deficiencies are associated with a 10,000-fold higher risk for life-threatening meningococcal infections in humans. Surprisingly, the complement system is redundant for defense against most pathogens except encapsulated bacteria. Newer concepts embrace the view that complement factors mediate functions inside cells either directly or through surface receptors. Complement activity fine-tunes homeostasis, metabolism and biogenesis. On the other hand, uncontrolled complement activation causes disease and can even worsen the outcome of infections. Toxic complement effectors mediate tissue destruction and organ injury during inflammatory diseases. Acute respiratory distress syndrome (ARDS) and sepsis are frequent and severe complications of acute infections and notorious for excessive complement consumption. The three pathways of complement activation are designed for immune sensing of non-self surfaces and foreign antigens. The mannose-binding lectin (MBL)/ficolin pathway starts with soluble pathogen pattern recognition receptors as sensors for foreign carbohydrate motifs (Fig. 1). The alternative pathway is fueled by a spontaneous ‘smoldering’ hydrolysis of C3 targeting all surfaces, unless these surfaces present complement inhibitory proteins (CD46, CD55, CD59) as a protective self-signal. This C3 ‘tick-over’ is sustained by the high concentrations of C3 in plasma (1-2 g/L) – the highest level of all complement factors. The classical pathway is initiated by antigen-antibody complexes which are recognized by the multimeric C1 complex. As a safeguard, IgG antibodies bound in clusters or pentameric IgM are required to surpass the activation threshold. All complement pathways converge on C3 convertase complexes leading to C3 cleavage into the larger C3b and the smaller anaphylactic C3a peptides. C3b is essential for the formation of C5 convertase for cleavage of C5 into C5b and the anaphylatoxin C5a. C5b is the starting point of the pore-forming membrane attack complex (MAC) consisting of C5b-C9 with a channel diameter of ~100 Å. The C3/C5 hub represents a gigantic amplification loop. The alternative C3bBb convertase (half-life ~3 min) cleaves additional C3, resulting in more C3bBb and so on and so forth. This enzymatic chain reaction can deposit millions of C3b molecules on target surfaces in a few seconds. It is no surprise that such explosive events need to be tightly regulated to maintain the delicate balance of effective and justified pathogen attack, while avoiding damage of innocent bystander cells.

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 mannose-binding lectin (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, 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 membrane-attack complex (MAC, C5b-C9) and generate anaphylatoxins (C3a, 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. Abbreviations: 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.

https://immunology.sciencemag.org/content/6/59/eabj1014