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© The Rockefeller University Press, 0022-1007/1997/11/1689/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 10, November 17, 1997 1689-1699

Articles

Antibodies that Inhibit Malaria Merozoite Surface Protein–1 Processing and Erythrocyte Invasion Are Blocked by Naturally Acquired Human Antibodies

José A. Guevara Patiño*, Anthony A. Holder*, Jana S. McBride{ddagger}, and Michael J. Blackman*

From the * Division of Parasitology, National Institute for Medical Research, London NW7 1AA, United Kingdom; and {ddagger} Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratories, Edinburgh EH9 3JT, United Kingdom

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-119) 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-119 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-119 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-119 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-119 target of processing-inhibitory antibodies; and (c) have the potential to abolish protection mediated by anti–MSP-119 antibodies. Our results suggest that an effective MSP-119–based falciparum malaria vaccine should aim to induce an antibody response that prevents MSP-1 processing on the merozoite surface.

Address correspondence to Dr. Michael J. Blackman, Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. Phone: 44-181-959-3666, ext. 2127; FAX: 44-181-913-8593; E-mail: mblackm{at}nimr.mrc.ac.uk

J.A. Guevara Patiño is in receipt of a studentship grant from the Venezuelan Government. J.S. McBride is supported by the Wellcome Trust. This investigation received financial support from the Medical Research Council (UK), and from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR).

1 Abbreviations used in this paper: EGF, epidermal growth factor; HRP, horseradish peroxidase–conjugated; MSP-1, merozoite surface protein–1; T, Tween 20; TLCK, tosyl-L-lysyl choromethyl ketone.


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