Targeting the Complement Cascade in the Pathophysiology of COVID-19 Disease

Abstract

Severe coronavirus disease 2019 causes multi-organ dysfunction with significant morbidity and mortality. Mounting evidence implicates maladaptive over-activation of innate immune pathways such as the complement cascade as well as endothelial dysfunction as significant contributors to disease progression. We review the complement pathways, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on these pathways, and promising therapeutic targets in clinical trials.

Keywords: COVID-19; SARS-CoV-2; complement inhibitor; complement pathway; lectin pathway; mannose-associated serine protease inhibitor.

Figure 1

Complement activation pathways. The classical pathway is activated by the binding of antibody-antigen complex with the C1 esterase complex (C1qC1rC1s), which then forms C3 convertase (C4b2a). The lectin pathway is initiated by the binding of mannose-binding lectin with mannose residues on pathogen surfaces, which activates mannose-associated serine proteases (MASPs) to form the same C3 convertase (C4b2a). The alternative pathway is triggered directly by antigen and also through spontaneous autoactivation, leading to the formation of a similar C3 convertase (C3bBb). These C3 convertases hydrolyze C3 to yield the C5 convertases (C4b2a3b and C3bBbC3b, respectively), which culminates in the generation of C5b-9 or MAC (membrane attack complex).

Figure 2

Integration between the complement and coagulation cascades. Relationship between the complement and coagulation cascades, as well as platelet activation is highlighted. Most notable are the effects of MASPs on thrombin, factor XIIIa, and fibrinogen; C5a on tissue factor; and C5b-9 on thrombin. Adapted from Hill et al. [23].

Figure 3

Mannose-binding lectin pathway and downstream effects. Initiation of the lectin pathway leads to the activation of MASP-1, which is capable of further autoactivation as well as activation of MASP-2. MASP-2 is responsible for the generation of subsequent anaphylatoxins and MAC. MASP-1 has much more relaxed substrate specificity, rendering additional effects in the coagulation and inflammatory cascades. Adapted from Dobo et al. [25].

Figure 4

Therapeutic targets in the complement cascade for the treatment of coronavirus disease 2019 (COVID-19) pneumonia.