Complement Evasion: An Effective Strategy That Parasites Utilize to Survive in the Host

Abstract

Parasitic infections induce host immune responses that eliminate the invading parasites. However, parasites have evolved to develop many strategies to evade host immune attacks and survive in a hostile environment. The complement system acts as the first line of immune defense to eliminate the invading parasites by forming the membrane attack complex (MAC) and promoting an inflammatory reaction on the surface of invading parasites. To date, the complement activation pathway has been precisely delineated; however, the manner in which parasites escape complement attack, as a survival strategy in the host, is not well understood. Increasing evidence has shown that parasites develop sophisticated strategies to escape complement-mediated killing, including (i) recruitment of host complement regulatory proteins on the surface of the parasites to inhibit complement activation; (ii) expression of orthologs of host RCA to inhibit complement activation; and (iii) expression of parasite-encoded proteins, specifically targeting different complement components, to inhibit complement function and formation of the MAC. In this review, we compiled information regarding parasitic abilities to escape host complement attack as a survival strategy in the hostile environment of the host and the mechanisms underlying complement evasion. Effective escape of host complement attack is a crucial step for the survival of parasites within the host. Therefore, those proteins expressed by parasites and involved in the regulation of the complement system have become important targets for the development of drugs and vaccines against parasitic infections.

Keywords: complement activation pathways; complement regulatory proteins; complement system; immune evasion; parasites.

FIGURE 1

Complement activation cascades and functions. (A) Immune complex (IC) activates the classical pathway through activating C1 complex (C1qr²s²). (B) PRMs such as MBL, ficolins and collectins, found in complexes with serine proteases (MASPs), bind to pathogen-associated molecular patterns (PAMPs) on the pathogen surface to activate the lectin pathway. Activation of the classical and lectin pathway leads to cleavage of C4 and C2 to form a C3 convertase (C4b2a). (C) The alternative pathway is initiated spontaneously by hydrolyzing C3 into C3(H₂O) with factors FB, FD and FP. This leads to the formation of C3 convertases of the alternative pathway [C3(H₂O)Bb or C3bBb]. Complement activation then comes to a core stage that C3 convertase cleave C3 into the anaphylatoxin C3a and the opsonin C3b. C3b then participates in the formation of the classical and lectin pathway C5 convertase (C4b2a3b) and the alternative pathway C5 convertase (C3bBbC3b). C5 convertase cleave C5 into the anaphylatoxin C5a and C5b. Afterwards, C5b assembles with C6, C7, C8, and multiple C9 molecules on the target surface to form MAC (C5b-9). MAC is a 10-nm aperture inserting into the target membrane, which results in the lysis of invading pathogens. The anaphylatoxins C3a and C5a bind to their corresponding receptors, C3aR and C5aR, to mediate inflammation. C3b triggers opsonization which facilitate phagocytic removal of the target. Complement modulates a variety of immune activities and acts as a linker between the native and the adaptive immune response such as augmentation of antibody response and enhancement of immunologic memory.

FIGURE 2

Regulation of complement activation by RCAs or parasite-expressed proteins targeting different complement components at the different steps of complement activation. Proteins showed in the blue boxes are human complement regulatory proteins. Proteins showed in the red boxes are parasites-generated to inhibit complement activation. (A) At the initiation step, C1 inhibitor binds to the active enzymes C1r/s and MASP-2 and dissociates them from C1q and MBL, respectively. Calreticulin, paramyosin, SMIPP-Ss, and N- and O-glycosylated molecules expressed by parasitic protozoa or helminths bind to C1q, MBL and ficolins to inhibit initiation of the classical and lectin pathway. (B) C3 convertase (C3bBb) undergoes an accelerated decay mediated by complement receptor 1 (CR1), decay accelerating factor (DAF), C4b-binding protein (C4BP) or factor H (FH). C3b is inactivated to iC3b by factor I (FI) with cofactor CR1, FH, C4BP or membrane cofactor protein (MCP). GP63 expressed by Leishmania binds to C3 leading to proteolysis of the active component C3b to form the inactive iC3b, thus preventing the formation of C3-convertase. GP58/68 expressed by T. cruzi binds with FB and interferes the formation of C3 convertase to inhibit alternative pathway. (C) Under normal conditions, CD59, S-protein (vitronectin), and Clusterin (SP-40) prevent the formation of the MAC. Paramyosin generated by helminth like T. spiralis bind with C8 and C9 to inhibit the formation of MAC.