CPB1

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Abstract

The global outbreak of coronavirus disease 2019 (COVID-19) has posed an unprecedented health crisis. As the pandemic continues and research advances, there is growing evidence that thrombosis and coagulopathy are fatal outcomes in COVID-19 patients. New data show that up to 49% of COVID-19 patients in the intensive care unit (ICU) develop thrombotic complications, and autopsies provide further direct evidence of pulmonary embolism in COVID-19 patients. Notably, immunothrombosis contributes to thrombotic events in coagulopathy, and the formation of neutrophil extracellular traps (NETs) composed of extracellular DNA decorated with granule proteins released by activated neutrophils is considered to be the leading cause of immune thrombosis. Therefore, uncovering the mechanisms that lead to the formation of NETs is critical to exploring more effective treatments against COVID-19.

Background

Complement is a major component of the innate immune system, and during complement activation, the central component C3 is cleaved into C3a and C3b. C3b binds to C3 convertase to form C5 convertase, which is responsible for the proteolysis of C5 into C5a and C5b. The anaphylatoxin C3a and C5a act as potent activators of neutrophil migration, cytokine production, platelet-leukocyte aggregation, and NET release by binding to receptors C3aR and C5aR on the surface of neutrophils. Recent studies have shown that complement C5a- and C3a-mediated NET formation is a key driver in COVID-19 immunothrombosis.

Notably, the carboxy-terminus of C3a and C5a contain arginine residues that are closely associated with optimal activity. Carboxypeptidases are capable of controlling the activity of anaphylatoxins by cleaving a C-terminal arginine residue to generate arginine derivatives (C3a_des-Arg and C5a_des-Arg). The resulting C5a_des-Arg retained 1%-10% of its original inflammatory activity, whereas C3ades-Arg did not have any pro-inflammatory activity. Recently, carboxypeptidase B2 (CPB2, encoded by the human CPB2 gene) was shown to be an important regulator in reducing inflammatory response and organ damage by degrading plasma anaphylatoxins.

Discussion

As one of the leading causes of mortality in severe COVID-19, thrombosis has received extensive attention, but the mechanism of its formation remains unclear. NETs have recently been found to be key factors in pathogenesis. A study investigated the longitudinal dynamics of complement C3, C5, and NETs in the plasma of patients of mild and severe COVID-19 disease over a period of up to 60 days.

First, the study found that elevated levels of NETs and complement C3 were strongly associated with immune status, coagulation disorders, and multiple organ dysfunction. Second, complement anaphylatoxins C3a and C5a can regulate NET formation. Third, recombinant CPB can improve the adverse effects of NETs on vascular endothelial cells by degrading C3a and C5a.

Numerous studies have shown that the activation of complement C3 and C5 is involved in the pathogenesis of COVID-19, and complement activation may lead to tissue damage and organ dysfunction in patients with COVID-19. Therefore, complement-blocking drugs may be a useful addition to the therapeutic armamentarium for COVID-19.

Several recently initiated clinical trials have used C5a inhibitors (Zilucoplan, NCT04382755) or anti-C5a antibodies (Eculizumab, NCT04288713) to prevent ARDS and control COVID-19 mortality. In addition to C5a, C3a was also significantly elevated in COVID-19 patients, suggesting that recombinant CPB could be used to degrade both C3a and C5a. Preclinical studies of recombinant CPB inhibiting uncontrolled inflammation and reducing the clinical severity of COVID-19 are worth looking forward to. Of note, endogenous CPB2, also known as a thrombin-activatable fibrinolysis inhibitor (TAFI), inhibits fibrinolysis and reduces the binding of plasminogen to the fibrin clot. Therefore, excessive supplementation of recombinant CPB may lead to an imbalance between coagulation and fibrinolysis. Therefore, the appropriate dose should be carefully considered in further studies. Studies have also shown that plasma-induced NET production in severe COVID-19 patients cannot be completely inhibited by neutralizing antibodies or recombinant CPB, implying that in addition to anaphylatoxins, other inducers of NETs remain to be discovered. Many studies have reported elevated levels of IL-6, IL-1β, and CXCL-8 in severe patients with COVID-19, which are also important factors in inducing granulocyte activation and NET release.