Antibodies that inhibit malaria merozoite surface protein-1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies

被引:190
作者
Guevara-Patino, JA
Holder, AA
McBride, JS
Blackman, MJ
机构
[1] NATL INST MED RES, DIV PARASITOL, LONDON NW7 1AA, ENGLAND
[2] UNIV EDINBURGH, INST CELL ANIM & POPULAT BIOL, ASHWORTH LABS, EDINBURGH EH9 3JT, MIDLOTHIAN, SCOTLAND
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1084/jem.186.10.1689
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Merozoite surface protein-1 (MSP-1) of the human malaria parasite Plasmodium falciparum undergoes at least two endoproteolytic cleavage events during merozoite maturation and release, and erythrocyte invasion. We have previously demonstrated that mAbs which inhibit erythrocyte Invasion and are specific for epitopes within a membrane-proximal, COOH-terminal domain of MSP-1 (MSP-1(19)) prevent the critical secondary processing step which occurs on the surface of the extracellular merozoite at around the time of erythrocyte invasion. Certain other anti-MSP-1(19) mAbs, which themselves inhibit neither erythrocyte invasion nor MSP-1 secondary processing, block the processing-inhibitory activity of the first group of antibodies and are termed blocking antibodies. We have now directly quantitated antibody-mediated inhibition of MSP-1 secondary processing and invasion, and the effects on this of blocking antibodies. We show that blocking antibodies function by competing with the binding of processing inhibitory antibodies to their epitopes on the merozoite. Polyclonal rabbit antibodies specific for certain MSP-1 sequences outside of MSP-1(19) also act as blocking antibodies. Most significantly, affinity-purified, naturally acquired human antibodies specific for epitopes within the NH2-terminal 83-kD domain of MSP-1 very effectively block the processing-inhibitory activity of the anti-MSP-1(19) mAb 12.8. The presence of these blocking antibodies also completely abrogates the inhibitory effect of mAb 12.8 on erythrocyte invasion by the parasite in vitro. Blocking antibodies therefore (a) are part of the human response to malarial infection; (b) can be induced by MSP-1 structures unrelated to the MSP-(19) target of processing-inhibitory antibodies; and (c) have the potential to abolish protection mediated by anti-MSP-1(19) antibodies. Our results suggest that an effective MSP-1(19)-based falciparum malaria vaccine should aim to induce an antibody response that prevents MSP-1 processing on the merozoite surface.
引用
收藏
页码:1689 / 1699
页数:11
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