Complement and Antibody-mediated Enhancement of Red Blood Cell Invasion and Growth of Malaria Parasites

Abstract

Plasmodium falciparum malaria is a deadly pathogen. The invasion of red blood cells (RBCs) by merozoites is a target for vaccine development. Although anti-merozoite antibodies can block invasion in vitro, there is no efficacy in vivo. To explain this discrepancy we hypothesized that complement activation could enhance RBC invasion by binding to the complement receptor 1 (CR1). Here we show that a monoclonal antibody directed against the merozoite and human polyclonal IgG from merozoite vaccine recipients enhanced RBC invasion in a complement-dependent manner and that soluble CR1 inhibited this enhancement. Sialic acid-independent strains, that presumably are able to bind to CR1 via a native ligand, showed less complement-dependent enhancement of RBC invasion than sialic acid-dependent strains that do not utilize native CR1 ligands. Confocal fluorescent microscopy revealed that complement-dependent invasion resulted in aggregation of CR1 at the RBC surface in contact with the merozoite. Finally, total anti-P. berghei IgG enhanced parasite growth and C3 deficiency decreased parasite growth in mice. These results demonstrate, contrary to current views, that complement activation in conjunction with antibodies can paradoxically aid parasites invade RBCs and should be considered in future design and testing of merozoite vaccines.

Malaria Parasites: The Great Escape

“…Antibodies against the P. falciparum asparagine-rich protein enhance merozoite invasion of RBC in vitro (106). Merozoite-specific antibodies in conjunction with complement can also facilitate RBC invasion (107). Antibody-dependent enhancement of infection was also observed in vivo after immunization with a Plasmodium berghei parasite blood-stage preparation which led to increased death after challenge (108).…”

Evaluating Complement-Mediated Humoral Immunity to P. falciparum Blood Stages

“…Data was presented showing a reduced level of inhibition mediated by sera from MSP1-42 vaccinated malaria-naïve human subjects in C3/ C 4 supplemented serum compared to C3/ C 4 depleted serum. However, in non-vaccinated controls, there was no difference in invasion between complement active and complement inactivated sera, as would be expected if complement activated sera significantly enhanced invasion and if MSP1-42 C-terminal antibodies augmented this effect (Biryukov et al, 2016). Further, while Biryukov et al support their findings with in vivo animal models using P .…”

“…While Biryukov et al propose that mouse monoclonal antibodies to MSP1-19 augment the enhancement effect of normal sera, the reported effect was only moderate when considering absolute parasitamias, and there appears to be large variability in the effect as seen across experimental replicates (data presented in the supplementary materials within Biryukov et al, 2016). Data was presented showing a reduced level of inhibition mediated by sera from MSP1-42 vaccinated malaria-naïve human subjects in C3/ C 4 supplemented serum compared to C3/ C 4 depleted serum.…”

“…Biryukov et al bring to our attention the potential ability of complement factors to enhance P . falciparum merozoite invasion in vitro (Biryukov et al, 2016). They proposed that i) complement activation at the merozoite surface enhanced the ability of merozoites to bind and invaded RBCs and ii) that antibodies to merozoite surface protein 1 (MSP1) C-terminal region further enhanced this process.…”

The Use of Filter-Purified Merozoites to Assess Anti-Merozoite Immunity

“…We have recently reported the enhancing effects of anti -merozite antibodies and complement interactions at promoting red blood cell invasion and growth by merozoites. We have observed this enhancement using both a traditional invasion assay and the Plasmodium berghei ANKA model of experimental malaria (Biryukov et al, 2016). Our results are in contradiction to those reported by Boyle et al (Boyle et al, 2015) who found that in the presence of complement, anti -merozoite antibodies are effective in preventing RBC invasion.…”