SARS-CoV-2 Infection and C1-Esterase Inhibitor: Camouflage Pattern and New Perspective.

In Covid-19, the pathological effect of SARS-CoV-2 infection is arbitrated through direct viral toxicity, unusual immune response, endothelial dysfunction, deregulated renin-angiotensin system [RAS], and thrombo-inflammation, leading to acute lung injury (ALI), with a succession of acute respiratory distress syndrome (ARDS) in critical conditions. C1 esterase inhibitor (C1INH) is a protease inhibitor that inhibits the spontaneous activation of complement and contact systems and kinin pathway, clotting, and fibrinolytic systems. Therefore, targeting the complement system through activation of C1INH might be a novel therapeutic modality in the treatment of Covid-19. Therefore, this study aims to illustrate the potential nexus between C1INH and the pathophysiology of SARS-CoV-2 infection. C1INH is highly dysregulated in Covid-19 due to inflammatory and coagulation disorders. C1INH is up-regulated in Covid-19 and sepsis as an acute phase response, but this increase is insufficient to block the activated complement system. In addition, the C1INH serum level predicts the development of ARDS in Covid-19 patients, as its up-regulation is associated with the development of cytokine storm. In Covid-19, C1INH might be inhibited or dysregulated by SARS-CoV-2, leading to propagation of complement system activation with subsequent uncontrolled immunological stimulation due to activation of bradykinin and FXII with sequential activation of coagulation cascades and polymerization of fibrin. Thus, suppression of C1INH by SARS-CoV-2 infection leads to thrombosis and excessive inflammation due to uncontrolled activation of complements and contact systems.

Gene variants of coagulation related proteins that interact with SARS-CoV-2.

Thrombosis is a recognized complication of Coronavirus disease of 2019 (COVID-19) and is often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms, by which some of these variants may contribute to disease, are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches.

Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex.

Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases.IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.

C1 esterase inhibitor and the contact system in COVID-19.

Coronavirus disease 2019 (COVID-19) is frequently associated with severe systemic consequences, including vasculitis, a hyperinflammatory state and hypercoagulation. The mechanisms leading to these life-threatening abnormalities are multifactorial. Based on the analysis of publicly available interactomes, we propose that severe acute respiratory syndrome coronavirus-2 infection directly causes a deficiency in C1 esterase inhibitor, a pathogen-specific mechanism that may help explain significant systemic abnormalities in patients with COVID-19.