Rationale for targeting complement in COVID-19

Abstract

A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.

Keywords: COVID-19; SARS-CoV-2; complement proteins; lectin pathway; therapeutics.

Figure 1

Genome and proteins of SARS‐CoV‐2.

Figure 2. Model of SARS‐CoV‐2 spike protein and glycosylation sites

The three protomers of the spike are shown in red, blue and white. The host cell receptor ACE‐2 is in orange. N‐glycosylation sites are displayed in green (on the spike) or yellow (on the receptor). Each cluster of spheres represents a single N‐acetylglucosamine residue (one sphere per atom), though the actual N‐linked glycan will consist of multiple sugar residues at each of the glycosylation sites. It can be seen that the spike has multiple N‐linked glycosylation sites (while the receptor only has three N‐linked sites). The model was generated by superposing structures PDB:6M0J (Lan et al, 2020) and PDB: 6VSB (Wrapp et al, 2020).

Figure 3. Models of the complement system

(A) Simplified scheme of the complement and coagulation cascades and some of their interactions. The complement system comprises three main pathways: classical, lectin and alternative. The classical and lectin pathways are initiated through the action of pattern recognition molecules (PRM): C1q for the classical pathway; and collectins (e.g. CL‐11, collectin‐11; and MBL, mannose‐binding lectin) and ficolins for the lectin pathway. PRMs bind to pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs). Following this, cleavage of complement factors C4 and C2 generates C3 convertase (C4bC2b), which cleaves C3 to C3a and C3b. C3b binds factor B, which is cleaved by factor D to generate C3bBb, the alternative pathway convertase, which results in amplification of C3b from C3. The two C5 convertases (C4bC2bC3b and C3bBbC3b) cleave C5 into C5a and C5b, the latter alongside C6, C7, C8 and C9 forming the membrane attack complex (MAC) C5b‐9. Meanwhile, the other products of C3 cleavage (C3a and the end metabolite of C3b called C3d) and C5 cleavage (C5a) have a number of roles including opsonisation, inflammation and the recruitment of the adaptive immune system. In the coagulation cascade, prothrombin is converted to thrombin, which in turn converts fibrinogen to fibrin and factor XIII to factor XIIIa. Fibrin forms the structure of the blood clot, while the factor XIIIa stabilises this clot by cross‐linking fibrin. Cross talk between the complement system and the coagulation system occurs through the actions of the MBL‐associated serine proteases (MASPs). MASP‐2 can convert prothrombin to thrombin, while MASP‐1 can act like thrombin and convert fibrinogen to fibrin (adapted from Nauser et al, 2018; Shimogawa et al, 2017). For a more extensive review of complement–coagulation interactions, see (Lupu et al, 2014). (B) Schematic representation of relevant lectin pathway pattern recognition molecules and their oligomeric structures. CL‐11 and ficolins initially form trimeric subunits, which then combine to form oligomers. MBL forms trimers and tetramers of MBL subunits, but both higher (pentamers and hexamers) and lower forms (monomers and dimers) also occur (adapted from Garred et al, 2016; Selman & Hansen, 2012). CRD: carbohydrate recognition domain; FLD: fibrinogen‐like domain.

Figure 4. Hypothetical pathway for complement‐mediated inflammation of the pulmonary alveolus in COVID‐19

(1) SARS‐CoV‐2 attaches to type II alveolar epithelial cell (AEC‐II) receptor angiotensin‐converting enzyme 2 (ACE2). (2) Complement activation is initiated upon recognition of viral glycans by lectins (e.g. collectin‐11 and ficolin‐1, which are secreted by AEC‐II) complexed with MBL‐associated serine proteases (MASPs) including MASP‐2. Direct binding of MASP‐2 to the N protein of SARS‐CoV‐2 has also been suggested to initiate lectin pathway activation (preprint: Gao et al, 2020). (3) Complement deposition and MAC formation on AECs cause inflammasome activation and cell damage. (4) Release of complement C5a increases vascular permeability and recruitment/activation of polymorphs (PMN) and monocytes (MC) to the alveolus. (5) Monocytes differentiated into inflammatory macrophages (MΦ) overproduce pro‐inflammatory cytokines in response to C3a and C5a stimulation. (6) Endothelial cell (EC) activation by C5a and MAC predisposes to thrombus formation, further enhanced through MBL recognition of viral particles in the vascular compartment leading to cleavage of thrombin and fibrinogen by MASPs.