Journal of Clinical Medicine Review Targeting the Complement Cascade in the Pathophysiology of COVID-19 Disease Nicole Ng and Charles A. Powell * Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] * Correspondence: [email protected] Abstract: Severe coronavirus disease 2019 causes multi-organ dysfunction with significant morbidity and mortality. Mounting evidence implicates maladaptive over-activation of innate immune path- ways such as the complement cascade as well as endothelial dysfunction as significant contributors to disease progression. We review the complement pathways, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on these pathways, and promising therapeutic targets in clinical trials. Keywords: COVID-19; SARS-CoV-2; complement pathway; lectin pathway; complement inhibitor; mannose-associated serine protease inhibitor 1. Introduction Severe coronavirus disease 2019 (COVID-19) is a multi-system disorder characterized by microvascular dysregulation and thrombosis that causes acute respiratory distress Citation: Ng, N.; Powell, C.A. syndrome (ARDS), kidney injury, cardiomyopathy, and encephalitis. Evidence suggests Targeting the Complement Cascade that this is driven by exuberant host responses leading to maladaptive over-activation of in the Pathophysiology of COVID-19 innate immune pathways, most notably the complement cascade. Disease. J. Clin. Med. 2021, 10, 2188. https://doi.org/10.3390/jcm10102188 2. The Complement Cascade The complement cascade is a host defense system that traces its biologic origins to over Academic Editors: Philippe Guilpain one billion years ago [1]. This system consists of more than fifty plasma proteins that inter- and Maciej Markiewski act to sense and respond to invasive pathogens [2]. It is a component of the innate immune response that links the innate and adaptive responses. Activation occurs via one of three Received: 26 March 2021 Accepted: 14 May 2021 pathways—classical, lectin, or alternative pathway, that converge to form C5 convertase, as Published: 19 May 2021 well as numerous anaphylatoxins (Figure1). C5 convertase generates C5b-9, also known as membrane attack complex (MAC). MAC creates cytotoxic membrane channels leading Publisher’s Note: MDPI stays neutral to cell death; however, even sublytic concentrations have significant immunomodulatory with regard to jurisdictional claims in effects [3]. Anaphylatoxins produce a host of proinflammatory responses that range from published maps and institutional affil- increased vascular permeability to the activation and recruitment of leukocytes [4]. iations. The important role of the complement cascade in responding to viral infections is demonstrated by evolutionary evidence of specific mechanisms employed by viruses to evade the complement system [5,6]. These include piracy of host regulators of complement activation (e.g., complement factor H by Flaviviridae), viral mimicry of host complement- related proteins (e.g., Vaccinia viridae encoding of vaccinia virus complement control protein, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. VCP), or encoding of proteins to prevent complement mediated effects (e.g., Influenza A This article is an open access article encoding of matrix, M1, protein to prevent neutralization, or Variola viridae encoding distributed under the terms and smallpox inhibitor of complement enzyme, SPICE, to inhibit C3 convertase) [6–9]. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 2188. https://doi.org/10.3390/jcm10102188 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 13 J. Clin. Med. 2021, 10, 2188 2 of 13 FigureFigure 1. ComplementComplement activation activation pathways. pathways. The The classica classicall pathway pathway is activated is activated by the by binding the binding of ofantibody-antigen antibody-antigen complex complex with with the theC1 esterase C1 esterase complex complex (C1qC1rC1s), (C1qC1rC1s), which which then forms then formsC3 C3 convertaseconvertase (C4b2a). The The lectin lectin pathway pathway is initiate is initiatedd by the by binding the binding of mannose-binding of mannose-binding lectin lectinwith withmannose mannose residues residues on pathogen on pathogen surfaces, surfaces, which which activates activates mannose-associated mannose-associated serine serine proteases proteases (MASPs) to form the same C3 convertase (C4b2a). The alternative pathway is triggered directly by (MASPs) to form the same C3 convertase (C4b2a). The alternative pathway is triggered directly antigen and also through spontaneous autoactivation, leading to the formation of a similar C3 by antigen and also through spontaneous autoactivation, leading to the formation of a similar C3 convertase (C3bBb). These C3 convertases hydrolyze C3 to yield the C5 convertases (C4b2a3b and convertaseC3bBbC3b, (C3bBb).respectively), These which C3 convertasesculminates in hydrolyze the generation C3 to of yield C5b-9 the or C5 MAC convertases (membrane (C4b2a3b attack andcomplex). C3bBbC3b, respectively), which culminates in the generation of C5b-9 or MAC (membrane attack complex). The complement system’s role in innate immunity is an important first line of protectionThe complement against invading system’s pathogens. role in innate Impo immunityrtantly, isexcessive an important activation first line can of lead protec- to tionmaladaptive against invading host inflammatory pathogens. Importantly,responses with excessive life-threatening activation caneffects. lead Recent to maladaptive research host inflammatory responses with life-threatening effects. Recent research shows that shows that exuberant complement activation causes pathogenic systemic inflammatory exuberant complement activation causes pathogenic systemic inflammatory response syn- response syndrome, endothelial dysfunction, and multiorgan dysfunction [10–12]. drome, endothelial dysfunction, and multiorgan dysfunction [10–12]. 3.3. MethodologyMethodology andand LiteratureLiterature SearchSearch TheThe PubMedPubMed literature literature search search strategy strategy (initial (initial search search date 14 date August 14 August 2020 and 2020 updated and onupdated 14 April on 2021) 14 April combined 2021) free-textcombined keywords free-text COVID, keywords SARS-CoV-2, COVID, SARS-CoV-2, and complement. and Filterscomplement. for the searchFilters for were the applied, search were and theapplied, filters and included the filters humans included [species], humans English [species], [lan- guage],English and[language], journal articles and journal [article articles types]. The[article number types]. of searchThe number results totaledof search618 results items, includingtotaled 618 abstract items, only. including ClinicalTrials.gov abstract only. was ClinicalTrials.gov accessed, the search was strategy accessed, (initial the searchsearch datestrategy 14 August (initial 2020search and date updated 14 August on 14 2020 April and 2021) updated utilized on the14 April search 2021) terms utilized “COVID” the forsearch condition terms “COVID” or disease, for and condition “complement”. or disease, The and total “complement”. number of search The total results number totaled of 49.search With results the 667 totaled items 49. at hand,With the 667 cited items items at totaled hand, the 98, includingcited items 31 totaled original 98, articles, including 41 reviews,31 original 2 textbook, articles, 41 16 reviews, clinical trials, 2 textbook, and 8 websites.16 clinical trials, and 8 websites. 4.4. Complement inin SARS-CoV-1,SARS-CoV-1, MERS-CoVMERS-CoV TheThe understandingunderstanding ofof SARS-CoV-2SARS-CoV-2 hashas leveragedleveraged priorprior researchresearch inin SARSSARS causedcaused byby relatedrelated virusesviruses inin thethe beta-Coronaviridaebeta-Coronaviridae family,family, SARS-CoVSARS-CoV andand MiddleMiddle EastEast respiratoryrespiratory syndromesyndrome coronavirus (MERS-CoV) [13]. [13]. SARS-CoV SARS-CoV originated originated in in Guangdong, Guangdong, China, China, in in2002, 2002, causing causing 8422 8422 infections infections and and916 deaths, 916 deaths, with witha case a fatality case fatality rate of rate10.8% of [14]. 10.8% MERS- [14]. J. Clin. Med. 2021, 10, 2188 3 of 13 MERS-CoV originated in Saudi Arabia in 2012, causing 2468 infections and 851 deaths, with a case fatality rate of 34.4% [15]. SARS-CoV-2 emerged in December 2019 in Wuhan, China. By 17 April 2021, there were over 136.7 million confirmed cases and 3.0 million deaths, with a case fatality rate of 2.1% [16]. Gralinski and colleagues performed the first in vivo studies of SARS-CoV in C57BL/6J mice that showed complement activation as early as day 1 post-infection [11]. To determine whether this complement cascade response was protective or pathologic, they tested the impact of viral infection in C3-deficient (C3-/-) mice. C3-/- mice had equivalent viral loads as control mice, indicating that complement signaling is not necessary for SARS-CoV clearance in lung. Compared to controls, SARS-CoV-infected C3-/- mice exhibited less weight loss and respiratory dysfunction, as well as decreased inflammation as measured by neutrophils, monocytes, cytokines, and chemokines both on lung pathology as well as sera. These data suggest that SARS-CoV lung injury progression may be driven by complement activation. Jiang and