Complement Evasion Strategies of Viruses: An Overview

Abstract

Being a major first line of immune defense, the complement system keeps a constant vigil against viruses. Its ability to recognize large panoply of viruses and virus-infected cells, and trigger the effector pathways, results in neutralization of viruses and killing of the infected cells. This selection pressure exerted by complement on viruses has made them evolve a multitude of countermeasures. These include targeting the recognition molecules for the avoidance of detection, targeting key enzymes and complexes of the complement pathways like C3 convertases and C5b-9 formation - either by encoding complement regulators or by recruiting membrane-bound and soluble host complement regulators, cleaving complement proteins by encoding protease, and inhibiting the synthesis of complement proteins. Additionally, viruses also exploit the complement system for their own benefit. For example, they use complement receptors as well as membrane regulators for cellular entry as well as their spread. Here, we provide an overview on the complement subversion mechanisms adopted by the members of various viral families including Poxviridae, Herpesviridae, Adenoviridae, Flaviviridae, Retroviridae, Picornaviridae, Astroviridae, Togaviridae, Orthomyxoviridae and Paramyxoviridae.

Keywords: DNA viruses; RNA viruses; complement; complement evasion; immune evasion; innate immunity; pathogenesis; retroviruses.

FIGURE 1

Activation pathways of the complement system and their targeting by viruses. The complement system is activated primarily by three pathways – CP, LP, and AP. Upper panel: In the CP, antigen-antibody complexes formed on the pathogen surface are recognized by the C1 complex (1) whereas in the LP, specific carbohydrates on the pathogen surface are recognized by MBL/ficolin-MASP complex (2). Both these complexes, upon activation, cleave C4 and C2 that results in the generation of C4bC2a (CP/LP C3 convertase) (3). The CP/LP C3 convertase cleaves C3 into C3b and C3a, where C3b binds and opsonises the pathogen surface and C3a boosts the acquired immune responses (4). When C3b combines with the pre-existing CP/LP C3 convertase, it forms CP/LP C5 convertase (5). In the AP, spontaneous hydrolysis of native C3 by H₂O (tick-over process) results in the formation of C3b-like C3 [C3(H₂O)] (6), which binds factor B (FB) and upon cleavage by factor D (FD) forms the initial AP C3 convertase (7). The initial AP C3 convertase then cleaves C3 into C3b and C3a (8). The generated C3b molecules bind to the pathogen surface and initiate the formation of surface-bound AP C3 convertase, C3bBb, with the help of FB and FD (9). The surface-bound AP C3 convertase initiates the AP amplification loop (10) resulting in deposition of millions of C3b molecules onto the pathogen surface. Similar to the CP and LP, when C3b combines to the pre-existing AP C3 convertase, it forms the AP C5 convertase (11). Lower panel: The C5 convertases cleave C5 into C5b and C5a (12), where C5b binds to C6 and C7 to form a trimer (C5b-7) (13) that binds to the pathogen surface, while C5a boosts the acquired immune responses. Further binding of C8 to the trimer results in the formation of C5b-8 that penetrates the membrane (14). Finally, C9 binding to C5b-8 and its polymerization completes the MAC formation leading to lysis (15). These activation pathways are regulated at different steps by host complement regulators like factor H (FH), MCP (CD46) complement receptor-1 (CR-1; CD35), DAF (CD55) and C4b-binding protein (C4BP). Viral proteins that target these pathways are: VCP, SPICE, MOPICE, Kaposi’s sarcoma-associated herpesvirus inhibitor of complement activation (KAPOSICA); γ-HV68 RCA, HVS CCPH; non-structural protein 1 of Flaviviruses (NS1); non-structural protein 3/4A of Hepacivirus (NS3/4A); glycoprotein C of HSV-1 (gC-1) and -2 (gC-2), human astrovirus coat protein (CoPt) and M1 protein of INFLV (M1).

FIGURE 2

Complement evasion strategies of viruses. (A) Piracy of soluble host RCA. Viruses evade complement attack by recruiting soluble complement regulator, viz. complement factor H (FH) by members of the families Flaviviridae, Retroviridae, and Togaviridae. (B) Piracy of membrane-bound host RCA. During budding, many enveloped viruses (viz. members of Poxviridae, Herpesviridae, Flaviviridae, Retroviridae, Orthomyxoviridae, and Paramyxoviridae) recruit membrane-bound regulators like CD55, CD46, and CD59. (C) Encoding homologs of RCA (vRCA). Viruses belonging to the families Poxviridae and Herpesviridae have been shown to encode regulators which are homologs of the human RCA gene family proteins. These are expressed as soluble [C(a)] as well as membrane-bound [C(b)] proteins. (D) Use of complement regulators and receptors for cellular entry. Viruses of the families Herpesviridae, Adenoviridae, Flaviviridae, Retroviridae, Picornaviridae, and Paramyxoviridae are known to use complement receptors and regulators for cellular entry (e.g., CD35, CD21, CD11b/CD18, CD55, and CD46). (E) Encoding of unique complement regulatory proteins. Apart from vRCA, members of some virus families namely, Herpesviridae, Flaviviridae, and Astroviridae encode unique complement regulatory proteins for evading the complement system. (F) Modulation of complement protein expression. Viruses are also known to modulate complement proteins for their benefit. These include down-regulation of complement activation proteins [F(a)] and up-regulation of complement regulatory proteins [F(b)]. Members of Herpesviridae, Flaviviridae, and Paramyxoviridae are involved in up-regulation of host complement regulators, while that of Flaviviridae are known to down-regulate the expression of complement activation proteins. Key: CD55, decay-accelerating factor; CD46, membrane cofactor protein; vRCA, viral regulators of complement activation; CD35, CD21, CD11b/CD18, complement receptor-1, -2 and -3.