SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems

Abstract

Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins – the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood. In these studies, we used: solid phase ELISA, hemolytic assay and surface plasmon resonance (SPR) techniques to examine if recombinant proteins corresponding to S1, N, M and E: (a) bind to C1q, gC1qR, FXII and high molecular weight kininogen (HK), and (b) activate complement and/or the KKS. Our data show that the viral proteins: (a) bind C1q and activate the classical pathway of complement, (b) bind FXII and HK, and activate the KKS in normal human plasma to generate bradykinin and (c) bind to gC1qR, the receptor for the globular heads of C1q (gC1q) which in turn could serve as a platform for the activation of both the complement system and KKS. Collectively, our data indicate that the SARS-CoV-2 viral particle can independently activate major innate inflammatory pathways for maximal damage and efficiency. Therefore, if efficient therapeutic modalities for the treatment of COVID-19 are to be designed, a strategy that includes blockade of the four major structural proteins may provide the best option.

Pathophysiological Response to SARS-CoV-2 Infection Detected by Infrared Spectroscopy Enables Rapid and Robust Saliva Screening for COVID-19

“…Strikingly, our proteomics data revealed extensive upregulation of kallikrein proteins in the oral lavage of SARS-CoV-2 POS mice. Savitt et al recently reported direct interaction and activation of the kallikrein/kinin system (KKS) by recombinant SARS-CoV-2 proteins S, M, N, and E [ 44 ]. High molecular weight kininogen (HK) and plasma prekallikrein (PK) bring about the sequelae of bradykinin, and complexing of HK/PK with blood coagulation factor XII (FXII), initiate the intrinsic clotting cascade with the aid of misfolded proteins and polyphosphate [ 45 ].…”

Case Report: Severe Rhabdomyolysis and Multiorgan Failure After ChAdOx1 nCoV-19 Vaccination

“…Even though complement was not tested and abnormalities could not be excluded at that time, eculizumab, a C5 inhibitor, was administered. Furthermore, it has been suggested that a blockade of C5a may be crucial for inhibition of the cytokine storm ( 30 , 31 ). Up to date, none of the viruses implicated as possible triggers of myositis have been shown to directly infect muscle fibers.…”

How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment

“…The virus itself has been shown to bind MBL, Ficolin-2 and Collectin-11, via its S- and N-proteins, with subsequent LP-mediated C3b and C4b deposition ( 44 , 45 ). Structural parts of the virus have also been shown to bind C1q and trigger complement activation ( 43 ). COVID-19 is strongly associated with ischemic cells, apoptosis, and cell death ( 15 , 20 , 40 ), initially occurring in the lung tissue.…”

“…Multiple proinflammatory cytokines and chemokines such as TNF, IL-1b, IL-6, and MCP-1 are produced in response to C3a and C5a generation that further amplifies the production of acute-phase proteins (41,42). The IIIS activation is multifactorial: The virus itself can activate the IIIS directly via the CP and LP of the complement system and via the KK system (43)(44)(45). Another likely activation mechanism is tissue damage in the lungs with apoptotic and necrotic cells that initiates the overactivation of IIIS in its function to eliminate cells or cell debris (46).…”

“…In several early reviews and in vitro studies, the KK system was suggested to participate in the thromboinflammation of COVID-19 (43,(57)(58)(59), without presenting any evidence of KK system activation in vivo. No direct evidence of such activation was published until reports from us, and Busch et al showed strong KK system activation in severely ill ICU patients (1,60).…”