Complement in malaria: immune evasion strategies and role in protective immunity

Abstract

The malaria parasite has for long been thought to escape host complement attack as a survival strategy. However, it was only recently that complement evasion mechanisms of the parasite were described. Simultaneously, the role of complement in antibody-mediated naturally acquired and vaccine-induced protection against malaria has also been reported. Such findings should be considered in future vaccine design, given the current need to develop more efficacious vaccines against malaria. Parasite antigens derived from molecules mediating functions crucial for parasite survival, such as complement evasion, or parasite antigens against which antibody responses lead to an efficient complement attack could present new candidates for vaccines. In this review, we discuss recent findings on complement evasion by the malaria parasites and the emerging role of complement in antibody-mediated protection against malaria. We emphasize that immune responses to vaccines based on complement inhibitors should not only induce complement-activating antibodies but also neutralize the escape mechanisms of the parasite.

Keywords: Plasmodium; complement; immunity; malaria.

Fig. 1

Life cycle of the malaria parasite P. falciparum.

Fig. 2

Pathways of complement activation. The complement system forms the first line of defense against invading pathogens. It can be activated through three major pathways: the classical pathway, the lectin pathway, and the alternative pathway. Antigen–antibody complexes are recognized by C1q of the classical pathway, MBL and ficolins binding to foreign surfaces activate the lectin pathway, while spontaneous hydrolysis of native C3 will initiate the alternative pathway. Upon activation, there is initial deposition of C3b on the foreign surface, which will generate the actual alternative pathway C3bBb that boosts a feedback amplification loop. Through the formation of C3bBb, all pathways culminate in the formation of C3b and the anaphylatoxin C3a. Subsequent C5 convertase formation leads to C5b and anaphylatoxin C5a generation, with C5b initiating the formation of the MAC, which becomes inserted into target cell membranes. Host tissues and cells are protected from complement deposition by fluid‐phase and cell‐bound regulators. C1‐INH inhibits the functions of C1r, C1s, and MASP2. C3b (and C4b) is inactivated by complement factor I and one of several cofactor proteins (surface‐bound CD46 and complement receptor type 1 (CR1) or fluid‐phase factor H or C4BP). Convertases are regulated through disassembly by regulators that have decay‐accelerating activity (CD55, CR1, factor H, and C4BP). The formation of the MAC is controlled by the activities of CD59, clusterin, and vitronectin.

Fig. 3

Regulation of complement activity by the soluble regulators FH and C4BP. (A) FH and C4BP have decay‐accelerating activities for the alternative and classical C3bBb, respectively. (B) FH and C4BP act as cofactors promoting FI‐mediated cleavage of C3b and C4b.

Fig. 4

Schematic representation of the CCP domains of FH (1–20) and FHL‐1 (1–7). Binding sites for C3b, C3d, sialic acid, and heparin are shown by horizontal lines. FHL‐1 is a splice variant of FH.

Fig. 5

Model of complement evasion on parasite surface through acquisition of the soluble host complement regulator FH.

Fig. 6

Involvement of complement in the P. falciparum life cycle. (A) The life cycle of the P. falciparum parasite in mosquito and human (created with BioRender.com). Boxes highlight the developmental stages at which complement is inhibited by parasite molecules or provides protection to the parasite, when it is residing inside erythrocytes. (B) Sagittal section of a blood‐engorged Anopheles mosquito stained with hematoxylin and eosin (created in the senior author’s laboratory). Spontaneous hydrolysis of native C3 activates the alternative pathway. Upon activation, there is initial deposition of C3b on the midgut epithelium, which can also initiate a feedback amplification loop. Captured FH on the midgut epithelium acts as an accelerator of the decay of C3bBb and as a cofactor for factor I in the proteolytic inactivation of C3b to iC3b.