Subversion of complement by hematophagous parasites

Abstract

The complement system is a crucial part of innate and adaptive immunity which exerts a significant evolutionary pressure on pathogens. It has selected for those pathogens, mainly microorganisms but also parasites, that have evolved countermeasures. The characterization of how pathogens evade complement attack is a rapidly developing field of current research. In recent years, multiple complement evasion strategies have been characterized. In this review, we focus on complement escape mechanisms expressed by hematophagous parasites, a heterogeneous group of metazoan parasites that share the property of ingesting the whole blood of their host. Complement inhibition is crucial for parasite survival within the host tissue or to facilitate blood feeding. Finally, complement inhibition by hematophagous parasites may also contribute to their success as pathogen vectors.

FIG. 1

Diagrammatic representation of the activation pathways of the complement cascade. The complement system is a central host defence system of innate immunity and is activated immediately upon contact of a microbe with host body fluids. The activated complement system is highly toxic and can have devastating effects. Complement is activated by three pathways: the classical, the lectin and the alternative pathway. The classical pathway is initiated by antigen-antibody complexes. Upon complex formation, additional zymogens like C4 are activated and consequently form additional binding sites for other components of this cascade and for proteases. Upon cleavage e.g. by a serine protease, active enzyme complexes are generated, which form the classical pathway convertase C4b2b. The lectin pathway is initiated when the mannan binding lectin (MBL) binds to carbohydrates which are accessible on the surface of pathogens. After binding, MBL is activated by MBL associated serine proteases (MASPs) and consequently activates C4 and leads to C1 independent formation of the classical pathway convertase C4b2b. The alternative pathway is initiated by a spontaneous conformational change of the central complement component C3b which exposed its active thioester and by binding the additional component factor B. This complex C3bB is activated by the serine protease factor D in an active C3bBb complex which displays enzymatic activity. This C3 convertase initiates a powerful amplification reaction and generates more C3b molecules. All three pathways of complement activation merge at the level of C3 and form two different types of enzymes that cleave C3, i.e. C3 convertases (C3bBb and C4b2b). These act on C3 and generate the active component C3b and the anaphylactic and antimicrobial component C3a. C3b can act as an opsonin to enhance phagocytosis of a pathogen or particle by phagocytic cells which are equipped with specific C3 receptors (Complement Receptors CR1 to CR4). In addition, C3 formation can lead to the generation of a C5 convertase (C3b₂Bb or C4b2b3b) which cleaves C5 to form C5b as well as the anaphylactic and antimicrobial component C5a. C5b initiates the terminal pathway, by activating sequentially and non enzymatically the terminal complement components C6, C7, C8 and C9, resulting in formation of the membrane attack complex (MAC, also called the terminal complement complex). The end product of the MAC pathway is a pore, which is composed of multiple assembled C9 proteins. These insert into the membrane of the target and cause target/cell lysis and membrane disruption. The activated complement system generates highly toxic effects on target cells or surfaces. The complement system has an intrinsic control activity which ensures that activation proceeds on foreign particles, such as microbes, but is actively controlled and blocked on self cells, i.e. host cell surfaces. Multiple regulators control the action of the complement cascade and these are shown in blue. Regulators show a variable distribution: some are present in fluid phase, e.g. factor H, FHL-1 (factor H-like protein 1) and C4bp (C4 binding protein); and others are inserted into the membrane of the host cells, e.g. MCP/CD46 (membrane cofactor protein), CR1/CD35 (complement receptor 1) and DAF/CD55 (decay accelerating factor). C1-INH, the C1 inhibitor, is present in plasma in relative high concentrations and binds covalently to active C1s and C1r. The terminal pathway is controlled by three inhibitors: clusterin and protein S bind to soluble C5-7 complexes and prevent integration into the membrane, protectin/CD59 inhibits binding of C9 to the complex and thus polymerization. Several regulators like CR1, DAF and MCP act in the classical and also in the alternative pathway. CR1 and DAF favour dissociation of the C3bBb, as well as the C4b2b complexes and similarly MCP acts as cofactor for degradation of both C3b and C4b. The symbols (+) and (−) associated with each regulator illustrate its positive or negative effect on the indicated reaction, respectively. (*) Schistosome ntigenic turnover applies to all three activation pathways.

FIG. 2

Diagrammatic representation of reported subversion mechanisms of the complement cascade by hematophagous parasites. Hematophagous parasites known to inhibit complement activation are presented in red. The name of the molecule responsible for the inhibition (if known) is indicated in brackets. Interrogation mark means that the molecule has not been identified yet. The symbol (−) indicates a negative effect on the indicated reaction.

FIG. 3

Cross section through a male and female schistosome couple within a blood vessel of a mouse. The female is held in the gynaecophoric canal of the male. The bar is 0.5 mm. The tegumental covering of both parasites is intact and shows no evidence of overt immunological (e.g. complement-mediated) attack.