Abstract
BackgroundAntibodies are the main effector molecules in the defense against blood stages of the malaria parasite Plasmodium falciparum. Understanding the mechanisms by which vaccine-induced anti-blood stage antibodies work in protecting against malaria is essential for vaccine design and testing.MethodsThe effects of MSP-1p42-specific antibodies on the development of blood stage parasites were studied using microscopy, flow cytometry and the pLDH assay. To determine allele-specific effects, if present, allele-specific antibodies and the various parasite clones representative of these alleles of MSP-1 were employed.ResultsThe mode of action of anti-MSP-1p42 antibodies differs among the parasite clones tested: anti-MSP-1p42 sera act mainly through invasion-inhibitory mechanisms against FVO parasites, by either preventing schizonts from rupturing or agglutinating merozoites upon their release. The same antibodies do not prevent the rupture of 3D7 schizonts; instead they agglutinate merozoites and arrest the development of young parasites at the early trophozoite stage, thus acting through both invasion- and growth inhibitory mechanisms. The second key finding is that antibodies have access to the intra-erythrocytic parasite, as evidenced by the labeling of developing merozoites with fluorochrome-conjugated anti-MSP-1p42 antibodies. Access to the parasite through this route likely allows antibodies to exert their inhibitory activities on the maturing schizonts leading to their inability to rupture and be released as infectious merozoites.ConclusionThe identification of various modes of action by which anti-MSP-1 antibodies function against the parasite during erythrocytic development emphasizes the importance of functional assays for evaluating malaria vaccines and may also open new avenues for immunotherapy and vaccine development.
Highlights
Antibodies are the main effector molecules in the defense against blood stages of the malaria parasite Plasmodium falciparum
The mode of action of blood stage-specific antibodies depends on their antigen-specificity: they can bind to merozoites, opsonize and target them towards phagocytic cells of the host [4], or prevent
The p19 fragment remains attached to the merozoite surface through a GPI anchor [13] and is comprised of two epidermal growth factor (EGF)-like domains [14], which may have a role in the invading complex
Summary
Antibodies are the main effector molecules in the defense against blood stages of the malaria parasite Plasmodium falciparum. Natural immunity against malaria is based on the presence of antibodies directed against the blood stage parasite, as demonstrated by passive transfer experiments of immunoglobulins [1,2,3]. Antibodies against the asexual blood stage antigen Pf332 inhibit the intra-erythrocytic development of Plasmodium falciparum [6,7,8]. The major merozoite surface protein -1 (MSP-1) was identified in immune complexes from merozoite lysates, which provided the rationale for developing vaccines against this antigen [11]. The second processing event occurs immediately before invasion, resulting in the cleavage of the p42 molecule into a p33 and a p19 fragment. Serological studies have provided significant evidence to suggest that immune responses directed against the C-terminus of MSP-1 (MSP-119 and MSP-142) are associated with immunity in preclinical models [15,16,17,18], as well as from individuals residing in endemic areas [16,19]
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