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Complement Proteins As Soluble Pattern Recognition Receptors for Pathogenic Viruses

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Complement Proteins As Soluble Pattern Recognition Receptors for Pathogenic Viruses viruses Review Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses Valarmathy Murugaiah 1,†, Praveen M. Varghese 1,† , Nazar Beirag 1, Syreeta DeCordova 1, Robert B. Sim 2 and Uday Kishore 1,* 1 Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK; [email protected] (V.M.); [email protected] (P.M.V.); [email protected] (N.B.); [email protected] (S.D.) 2 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK; [email protected] * Correspondence: [email protected] or [email protected] † These authors contributed equally to this work. Abstract: The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion op- sonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mecha- Citation: Murugaiah, V.; Varghese, nisms to subvert complement recognition/activation by encoding several proteins that inhibit the P.M.; Beirag, N.; DeCordova, S.; Sim, complement system, contributing to viral survival and pathogenesis. This review focuses on these R.B.; Kishore, U. Complement complement-dependent and -independent interactions of complement components (especially C1q, Proteins as Soluble Pattern Recognition Receptors for Pathogenic C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses Viruses. Viruses 2021, 13, 824. and their consequences. https://doi.org/10.3390/v13050824 Keywords: innate immunity; complement system; complement evasion; DNA viruses; RNA viruses; Academic Editor: Reinhard Würzner retroviruses; cytokine storm Received: 7 April 2021 Accepted: 28 April 2021 Published: 2 May 2021 1. Introduction The innate immune system is characterised by its ability to distinguish between Publisher’s Note: MDPI stays neutral “self” and “non-Self”. The complement system plays a crucial part in the innate immune with regard to jurisdictional claims in surveillance against viruses through several mechanisms that prevent host viral infection. published maps and institutional affil- It can be activated through three pathways: the classical, the alternative, and the lectin, iations. depending upon the recognition subcomponents and the ligand that trigger its activation. The classical pathway is activated (Figure1) by either direct binding of complement component C1q to the invading pathogen’s surface, or the binding of IgM, IgG1, and IgG3 to the antigen’s surface and the subsequent binding of C1q to this immune complex. The Copyright: © 2021 by the authors. binding of C1q to either antibodies or pathogen surface triggers the autoactivation of serine Licensee MDPI, Basel, Switzerland. protease, C1r, which subsequently cleaves and activates another serine protease, C1s [1]. This article is an open access article This generates a C1-complex consisting of one molecule of C1q and two molecules each of distributed under the terms and C1r and C1s. The C1 complex then cleaves C4 and C2, generating C4a, C4b, C2a, and C2b. conditions of the Creative Commons The C4b and C2a bind to form the C4b2a complex, the C3-convertase [2–4]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Viruses 2021, 13, 824. https://doi.org/10.3390/v13050824 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 824 2 of 29 Viruses 2021, 13, x FOR PEER REVIEW 2 of 27 Figure 1.FigureActivation 1. Activation and regulation and regulation of the of classicalthe classical and and lectin lectin pathways pathways and their their targeting targeting by byvirally virally encoded encoded molecules. molecules. In In the classical pathway (CP), C1 complex recognizes the antigen-antibody complexes present on the viral surface (1). In the classicalthe lectin pathway pathway (CP), (LP), C1 MBL/ficolin complex recognizes-MASP complexes the antigen-antibody can recognise other complexes carbohydrate present patterns on on the the viral surfaces surface of vi- (1). In the lectin pathwayruses (2). (LP), Upon MBL/ficolin-MASP activation, these complexes complexes can cleave can C4 recognise and C2 (3a) other that can carbohydrate lead to the formation patterns of onC4bC2a the surfaces (CP/LP C3 of viruses (2). Uponconvertase) activation, (3b). these The C3 complexes convertase can further cleave cleaves C4 C3 and into C2 C3b (3a) and that C3a; can C3b lead is known to the to formation opsonise th ofe viral C4bC2a surfac (CP/LPes, C3 whereas C3a can lead to an enhanced acquired immune responses (4). C3b-C3 convertase interaction can generate C5 convertase) (3b). The C3 convertase further cleaves C3 into C3b and C3a; C3b is known to opsonise the viral surfaces, convertase (5), which cleaves C5 into C5b and C5a (6). C5b further interacts with C6 and C7 (C5b-7) (7) that can bind to whereas C3athe viral can surface, lead to while an enhancedC5a induces acquiredfurther infiltration. immune C5b responses-7 then binds (4). to C3b-C3C8, which convertase can generate interaction C5b-8 that penetrates can generate C5 convertasethe (5), membrane which cleaves(8). Finally, C5 intothe C9 C5b binds and to C5athe C5b (6).-8 C5b and furtherresults in interacts MAC formation with C6 leading and C7 to (C5b-7)the virolysis (7) that(10). canThese bind to the viral surface,activation while pathways C5a induces are regulat furthered at infiltration. different steps C5b-7 by host then complement binds to C8, regulators which such can generateas C1 inhibitor, C5b-8 C4b that-binding penetrates the protein (C4BP), complement receptor 1 (CR1; CD35), membrane cofactor protein (MCP; CD46), decay-accelerating factor membrane(DAF; (8). CD55), Finally, and the CD59. C9 binds Viral toproteins the C5b-8 that target and resultsthese pathways in MAC are: formation Vaccinia virus leading complement to the virolysis control protein (10). These (VCP), activation pathwaysSmallpox are regulated inhibitor at of different complement steps enzymes by host (SPICE), complement Monkeypox regulators inhibitor such of complement as C1 inhibitor, enzymes C4b-binding (MOPICE), Kaposi’s protein (C4BP), complementsarcoma receptor-associated 1 (CR1; herpesvirus CD35), membraneinhibitor of complement cofactor protein activation (MCP; (KCP), CD46), Murine decay-accelerating gamma-herpesvirus factor 68 regulator (DAF; CD55),of and complement activation (γ-HV68 RCA), Herpesvirus saimiri complement control protein homologue (CCPH), Herpesvirus CD59. Viralsaimiri proteins CD59 thathomologue target (HVS these CD59), pathways Flavivirus are: Vaccinianon-structural virus protein complement 1 (NS1), HSV control-1 glycoprotein protein (VCP), C (gC Smallpox-1), human inhibitor of complementastrovirus enzymes coat protein (SPICE), (CoPt), Monkeypox and Influenza inhibitor virus matrix of complementprotein 1 (M1).enzymes These are identified (MOPICE), as black/grey Kaposi’s protein sarcoma-associated with herpesviruswhite inhibitor text, and of pink complement inhibitory arrows activation mark the (KCP), regulator Murine they gamma-herpesvirusinhibit. 68 regulator of complement activation (γ-HV68 RCA), Herpesvirus saimiri complement control protein homologue (CCPH), Herpesvirus saimiri CD59 homologue The lectin pathway is a homologue of the classical pathway. It is triggered by the (HVS CD59), Flavivirus non-structuralbinding protein of mannan 1 (NS1),-binding HSV-1 lectin glycoprotein (MBL) and C (gC-1),ficolins human to carbohydrate astrovirus patterns coat protein on the (CoPt), and Influenza virus matrix proteinpathogen 1 (M1). surface These areor carbohydrate identified as black/greystructures on protein antibodies, with including white text, the and common pink inhibitory IgG arrows mark the regulator they inhibit.glycosylation variant IgG-G0 and polymeric IgA [1,5–8]. In serum, MBL is found com- plexed with homologues of C1r and C1s, called MBL-associated serine proteases (MASPs) [1,9]The. lectinUpon MBL pathway binding is ato homologue a target, MASP of the-1 and classical MASP- pathway.2 autoactivate It is independently. triggered by the bind- ing ofMASP mannan-binding-2 cleaves C4 and lectin C2, triggering (MBL) and the ficolins formation to of carbohydrate the C3-conver patternstase similar on to the the pathogen surfaceclassical or carbohydrate pathway. structures on antibodies, including the common IgG glycosylation variant IgG-G0 and polymeric IgA [1,5–8]. In serum, MBL is found complexed with homo- logues of C1r and C1s, called MBL-associated serine proteases (MASPs) [1,9]. Upon MBL binding to a target, MASP-1 and MASP-2 autoactivate independently. MASP-2 cleaves C4 and C2, triggering the formation of the C3-convertase similar to the classical pathway. A distinct mechanism (Figure2) activates the alternative pathway. It has both antibody- dependent (IgG) and antibody-independent
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