Merozoite surface protein-3: a malaria protein inducing antibodies that promote Plasmodium falciparum killing by cooperation with blood monocytes

Abstract

We have previously found that the acquired protection against malaria implicates a mechanism of defense that relies on the cooperation between cytophilic antibodies and monocytes. Accordingly, an assay of antibody-dependent cellular inhibition (ADCI) of parasite growth was used as a means of selecting for molecules capable of inducing protective immunity to malaria. This allowed us to identify in the sera of clinically protected subjects an antibody specificity that promotes parasite killing mediated by monocytes. This antibody is directed to a novel merozoite surface protein (MSP-3) of a molecular mass of 48 kD. Purified IgG from protected subjects are effective in ADCI and those directed against MSP-3 are predominantly cytophilic. In contrast, in nonprotected individuals, whose antibodies are not effective in ADCI, anti-MSP-3 antibodies are mostly noncytophilic. A region in MSP-3 targetted by antibodies effective in the ADCI assay was identified and its sequence was determined; it contains an epitope not defined by a repetitive structure and does not appear to be polymorphic. Antibodies raised in mice against a peptide containing this epitope, as well as human antibodies immunopurified on this peptide, elicit a strong inhibition of Plasmodium falciparum growth in ADCI assay, whereas control antibodies, directed to peptides from other molecules, do not. The correlation between isotypes of antibodies produced against the 48- kD epitopes, clinical protection, and the ability of specific anti-MSP- 3 antibodies to block the parasite schizogony in the ADCI assay suggests that this molecule is involved in eliciting protective mechanisms.

Antibodies to a merozoite surface protein promote multiple invasion of red blood cells by malaria parasites

“…Alternatively, antibody cross-linked merozoites, drawn to the same rbc, may subsequently dissociate and invade the same rbc independently. It is not known whether antibodies to MSA1, or any of the other 40-48 kDa proteins detected more recently on the merozoite plasma membrane (Oeuvray et al 1994, Marshall et al 1998) similarly enhance multiple invasion. There is no information presently available on the comparative numbers of viable merozoites produced by rbcs infected with one or several rings, which in turn will determine whether multiple invasion promotes or hinders the development of malaria in vivo.…”

Antigenic Diversity of Plasmodium falciparum and Antibody‐Mediated Parasite Neutralization

“…P. falciparum antigens demonstrated as targets in ADCI assays include the merozoite surface protein 3 (MSP-3) [56], the glutamate-rich protein (GLURP) [57], Pf155/RESA (Wa Êhlin Flyg et al unpublished) and Pf332 [58]. The latter antigen is expressed on the surface of erythrocytes infected with late stages of P. falciparum, and a substantial part of the parasite inhibition in the ADCI was owing to phagocytosis of infected erythrocytes (Wa Êhlin Flyg et al unpublished).…”

“…The latter antigen is expressed on the surface of erythrocytes infected with late stages of P. falciparum, and a substantial part of the parasite inhibition in the ADCI was owing to phagocytosis of infected erythrocytes (Wa Êhlin Flyg et al unpublished). While antibodies to Pf155/ RESA and Pf332 also inhibit merozoite invasion and parasite growth, respectively, on their own [8], antibodies to MSP-3 and GLURP need the co-operation with monocytes in order to be inhibitory [56,57].…”

Vaccine candidate discovery for the next generation of malaria vaccines

“…Adapted from the WHO Rainbow Tables http://www.who.int/im munization/research/development/Rainbow_tables/en/. [44][45][46]54,56,58,59,61,[105][106][107][108][109][110][111][112][113][114][115][116][117] opportunity for the systematic interrogation of the entire parasite genome to identify potential targets of protective immunity at scale. The term 'antigen discovery' is now potentially a misnomer as genomes have been annotated and practically all antigens in effect are 'known'.…”