key: cord-0734394-pujliph5 authors: Thomson, Timothy M; Toscano, Emily; Casis, Ernesto; Paciucci, Rosanna title: C1‐INH and the contact system in COVID‐19 date: 2020-06-12 journal: Br J Haematol DOI: 10.1111/bjh.16938 sha: 4720796b3523b3d81e0056372b985c061e77cda1 doc_id: 734394 cord_uid: pujliph5 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 SARS‐CoV‐2 infection directly causes a deficiency in C1 esterase inhibitor (C1‐INH), a pathogen‐specific mechanism that may help explain significant systemic abnormalities in COVID‐19 patients. 2 are attributed to the cytokine storm accompanying severe inflammatory syndrome 7-9 , direct viral disruption of endothelial integrity 10 , release of coagulation factors by inflammasome-activated macrophages 11 , liver dysfunction 12 , antiphospholipid antibodies 13 , hypertension, hypoxia, stress from mechanical ventilation, limited mobility of the patients, or a combination of factors. While examining the published interactomes of SARS-CoV (Ref. 14 ) and SARS-CoV-2 (Ref. 15 ) proteins (hereafter, CoV1 and CoV2, respectively) with human proteins, we noted that C1-INH (C1 esterase inhibitor, encoded by the SERPING1 gene) is an interactor for 7 distinct CoV1 proteins and polypeptides, encoded by ORF3b, ORF7b, ORF14, nsp2ab, nsp13ab, nsp14ab and nsp8ab Of the SERPING1 CoV interactors, nsp8, together with nsp7, functions as a primase that forms part of the RNA polymerase complex 16 , nsp13 is a helicase 17 , nsp14 is a proofreading exoribonuclease 18 and an S-adenosyl methionine (SAM)-dependent (guanine-N7) methyl transferase 19 , the protein encoded by ORF3b antagonizes interferon responses through as yet uncharacterized molecular mechanisms 20,21 , the protein encoded by ORF7b bears a transmembrane domain through which it localizes to the Golgi complex and whose expression upon viral infection can lead to aberrant localization of cell-surface glycoproteins 22 and ORF14 encodes a 70 (CoV1) or 73 (CoV2) aminoacid protein for which no function has been described. We speculate that the likelihood of a direct interaction of with SERPING1 is lower for nsp7, nsp13 and nsp14, given their above-described functions, although the formation of multimolecular complexes remains a possibility. The 105-KDa glycoprotein C1-INH, a serine protease inhibitor bearing a conserved SERPIN domain, is the main inhibitor of the classical complement enzymes C1r and C1 esterase (C1s) 23 . It is also the primary inhibitor of the activated factors XII (FXIIa) and XI (FXIa) and activated plasma kallikrein (PKa) 23 and, more modestly, of plasmin, tissue-type plasminogen activator (tPA) and thrombin (Fig. 2) . C1-INH is the sole natural inhibitor of C1r and C1s, is an inhibitor of the lectin pathway of complement activation via inactivation of mannan-binding lectin-associated serine proteinase-1 and 2 (MSP1 and MSP2), and inhibits the alternative pathway of activation by binding to C3b. Thus, C1-INH is a major regulator of all three pathways of complement activation 24 . C1-INH is the most heavily glycosylated plasma protein, and bears a sialyl Lewis x -related moiety through which it binds to endothelial cell-surface selectins E and P, in competition with the binding of leukocytes 25 , exerting, as such, an anti-inflammatory function. Through covalent bond formation with the complement components C1s, C1r, MASP1 and MASP2 and reversible binding to C3a (Ref. 24 ), C1-INH attenuates the consequences of complement activation, including the generation of proinflammatory anaphylatoxins, especially C5a, and the formation of a membrane attack complex (MAC) that leads cell lysis. Of note, severe acute respiratory distress syndrome in SARS was found associated with excessive activation of C3 (Ref. 26 ). Further, MSP2 has been found to be a target of the N protein of MERS-CoV, SARS-CoV and SARS-CoV-2 (Ref. 27 ), and a blocking antibody to C5a has shown benefit in patients COVID-19 with severe lung injury. The presence of pulmonary edema is another feature COVID-19 patients with acute respiratory distress syndrome, and aberrant activation of the kallikreinbradykinin system has been proposed as an explanatory mechanism 28 The plasma contact system is a procoagulant and proinflammatory protease 4 cascade that occurs on the surface of endothelial cells 33 . Upon contact with surface-bound negatively charged polymers such as polyphosphate (polyP), proteoglycans or RNA, FXII is activated to catalyze the proteolytic activation of plasma kininogen (PK) to PKa which, in turn, converts high-molecular-weight kininogen (HK) to bradykinin (BK) 23 (Fig. 1d) . FXII also binds to the endothelial cell surface through interactions with the urokinase receptor (uPAR) or integrins Upon contact activation, FXIa sets off the coagulation cascade through sequential activation of factors X, IX and prothrombin (factor II), resulting in the polymerization of fibrin from fibrinogen. Incidentally, factor Xa cleaves the spike protein (S) of CoV1 at the S1-S2 boundary, enhancing the fusion of viral particles to cell membranes 36 . It has not yet been determined if the CoV2 spike protein, which is cleaved at the S1-S2 boundary by TMPRSS2 (Ref. 37 This article is protected by copyright. All rights reserved. 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