C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

Abstract

From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.

Keywords: C1 esterase inhibitor; C1 esterase inhibitor, C1-INH; C1-INH; COVID-19; Complement; FXII; Inflammation; Middle East respiratory syndrome coronavirus, MERS-CoV; Mycobacterium tuberculosis, Mtb; Severe acute respiratory syndrome coronavirus, SARS-CoV; acquired C1-INH deficiency, AEE; activated plasma kallikrein, PKa; antibody-mediated rejection, AMR; bradykinin, BK; contact system, CS; coronavirus disease 2019, COVID-19; exogenous C1-INH, exC1-INH; hereditary angioedema, HAE; high-molecular-weight kininogen, HK; human immunodeficiency virus, HIV; interferon, IFN; interleukin, IL; ischemia/reperfusion injury, IRI; mannose-binding lectin, MBL; prekallikrein, PK; recombinant C1-INH, rhC1-INH; serine protease inhibitor, serpin; tuberculosis, TB.

Fig. 1

C1-INH suppresses the contact system (CS) and complement activation. Activation of the CS drives bradykinin inflammation, coagulation, and fibrinolysis. C1-INH is the major plasma inhibitor of activated Factor XII and plasma kallikrein, proteins that initiate the CS and bradykinin inflammation, respectively. Similarly, C1-INH suppresses complement activation that drives host antiviral defenses by inhibiting proteins that initiate the proteolytic cascades of the classical and lectin pathways. Further, C1-INH inhibits the alternate pathway by binding C3b. Crosstalk between complement and the CS is mediated through thrombin-mediated complement activation of C3 and C5.

Fig. 2

Overview of endogenous immunosuppression and clinical uses of exogenous C1-INH. Physiological C1-INH inhibits CS and complement pathways, and these activities have been leveraged for clinical benefit through utilization of exogenous C1-INH (exC1-INH). Deficient C1-INH activity results in angioedema, and in patients with hereditary angioedema (HAE), this effect is largely attributed to unregulated bradykinin signaling, and treatment with exC1-INH is often used to manage disease-associated attacks. Animal models of ischemia/reperfusion injury (IRI) have shown that exC1-INH protects from inflammation and decreases immune cell recruitment. Clinical trial results from exC1-INH treatment in human solid organ transplant studies suggests that exC1-INH may decrease IRI and antibody-mediated rejection (AMR) in transplant recipients. Clinical use of recombinant C1-INH (rhC1-INH) is currently in development to treat or prevent bradykinin and cytokine storms in COVID-19 patients. Lines with arrows indicate activation, and lines with a perpendicular line indicate inhibition.

Fig. 3

Proposed C1-INH signaling in severe and mild COVID-19 patients. A. In mild COVID-19 patients studies suggest that IFN responses are intact and innate immune responses are sufficient to suppress SARS-CoV-2 infection. C1-INH levels increase in mild COVID-19 patients and may be responsible for the attenuation of hyperinflammatory activation. B. Studies suggest that insufficient Type I IFN signaling and high SARS-CoV-2 viral titer are associated with early phases of severe COVID-19. Paradoxically, increased immunosuppressant C1-INH levels correlate with COVID-19 severity. Severe COVID-19 patients suffer from cytokine and bradykinin storms, and the associated IFNγ release may potently induce SERPING1-encoded C1-INH. We speculate that SARS-CoV-2 expresses viral proteins that may bind C1-INH impairing its function and clearance from circulation. Non-functional C1-INH is unable to inhibit hyperinflammation, hypercoagulability, and aberrant complement activation contributing to severe COVID-19.