Cross–reactivity of antibody against an epitope of the <i>Plasmodium falciparum</i> second merozoite surface antigen

Saul, Allan; Lord, Roger; Jones, Graham L.; Hm, Geysen; Gale, Julie; Mollard, Rodney

doi:10.1111/j.1365-3024.1989.tb00923.x

Cited by 38 publications

(28 citation statements)

References 13 publications

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“…8G10, which is reactive with the FC27 central variable region, labeled newly invaded rings to a higher degree than other antibodies, but this labeling was still minimal compared to the labeling of merozoites prior to, during, or immediately after invasion. This may indicate that the epitopes recognized by this antibody are more accessible or degraded more slowly than other epitopes, or the labeling seen may reflect the cross-reactivity of this MAb, which was reported previously (71).…”

Section: Resultssupporting

confidence: 71%

“…The specificity of the MAbs to MSP2 was previously confirmed via Western blotting; all MAbs were specific to MSP2, with no cross-reactivity to other parasite proteins, except for MAb 9G8, which has some cross-reactivity to spectrin (60). 8G10 was reported previously in other studies to be cross-reactive to some extent with other parasite proteins, which have not been identified (71). As we lacked a MAb against the N-terminal region of MSP2 that reacted with the native surfacelocated antigen by IF microscopy, N-terminally specific antibodies were purified from rabbit polyclonal serum that had been generated by vaccination with full-length 3D7 MSP2.…”

Section: Resultssupporting

confidence: 62%

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Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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e Plasmodium falciparum causes malaria disease during the asexual blood stages of infection when merozoites invade erythrocytes and replicate. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to erythrocytes, but precise roles remain undefined. Based on electron microscopy studies of invading Plasmodium merozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, serine repeat antigen 4 (SERA4), and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the glycosylphosphatidylinositol (GPI)-anchored proteins MSP2 and MSP4 are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within 10 min, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed upon invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intraerythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into erythrocytes and maintained for approximately 20 h without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.

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Section: Resultssupporting

confidence: 71%

Section: Resultssupporting

confidence: 62%

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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“…Immune selection would be consistent with the diversity seen in AMA1, 44 and inefficient antibody responses are elicited to the repeat regions of the other antigens studied. 45,46 Therefore, the significant change in isolate genotype between the first and the fourth time points of this study is notable. We have shown that the dominant strain from the first time point is initially involved in infections throughout the study region.…”

Section: Discussionmentioning

confidence: 77%

Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity.

Eisen

Saul²,

Fryauff³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Many of the asexual stage Plasmodium falciparum proteins that are the targets of host protective responses are markedly polymorphic. The full repertoire of diversity is not defined for any antigen. Most studies have focused on the genes encoding merozoite surface proteins 1 and 2 (MSP1, MSP2). We explored the extent of diversity of some of the less studied merozoite surface antigens and analyzed the degree of complexity of malaria field isolates by deriving nucleotide sequences of several antigens. We have determined the genotype of apical membrane antigen 1 (AMA1) in a group of 30 field samples, collected over 29 months, from individuals living in an area of intense malaria transmission in Irian Jaya, identifying 14 different alleles. AMA1 genotyping was combined with previously determined MSP2 typing. AMA1 had the greatest power in distinguishing between isolates but methodological problems, especially when mixed infections are present, suggest it is not an ideal typing target. MSP1, MSP3, and glutamate-rich protein genotypes were also determined from a smaller group of samples, and all results were combined to derive an extended antigenic haplotype. Within this subset of 10 patients, nine different genotypes could be discerned; however, five patients were all infected with the same strain. This strain was present in individuals from two separate villages and was still present 12 months later. This strain was predominant at the first time point but had disappeared at the fourth time point. This significant change in malaria genotypes could be due to strain-specific immunity developing in this population.

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“…Early studies showed that mouse monoclonal antibodies (MAbs) that discriminated between heterologous parasites affected homologous in vitro growth inhibition (7,13). Curiously, there is scant evidence of the inability of allele-specific MAbs to inhibit heterologous parasites in vitro (45).…”

mentioning

confidence: 99%

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Stubbs¹,

Olugbile

Balam

et al. 2011

Infect Immun

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It is widely accepted that antibody responses against the human parasitic pathogen Plasmodium falciparum protect the host from the rigors of severe malaria and death. However, there is a continuing need for the development of in vitro correlate assays of immune protection. To this end, the capacity of human monoclonal and polyclonal antibodies in eliciting phagocytosis and parasite growth inhibition via Fc␥ receptor-dependent mechanisms was explored. In examining the extent to which sequence diversity in merozoite surface protein 2 (MSP2) results in the evasion of antibody responses, an unexpectedly high level of heterologous function was measured for allele-specific human antibodies. The dependence on Fc␥ receptors for opsonic phagocytosis and monocyte-mediated antibody-dependent parasite inhibition was demonstrated by the mutation of the Fc domain of monoclonal antibodies against both MSP2 and a novel vaccine candidate, peptide 27 from the gene PFF0165c. The described flow cytometry-based functional assays are expected to be useful for assessing immunity in naturally infected and vaccinated individuals and for prioritizing among blood-stage antigens for inclusion in blood-stage vaccines.Merozoite surface protein 2 (MSP2) is a leading Plasmodium falciparum vaccine candidate. Antibody responses to MSP2 have been associated with protection from malaria in humans (1,11,37,43,50,53) and afford protection in mouse models (35,46). However, extreme sequence diversity in MSP2 is considered an obstacle for vaccine design. Hundreds of alleles encoding MSP2 are classified into two main allelic families represented by the 3D7 and FC27/D10 MSP2 sequences (15,28,49,57). The coexistence of parasites bearing the dimorphic alleles at similar frequencies in globally disparate locations indicates their maintenance by selective pressures (9). Given that MSP2 is a blood-stage antigen, it is considered likely that sequence diversification may be driven by the host immune response by allele-specific antibodies. Consistent with this hypothesis, vaccine recipients in the Combination B phase IIb vaccine trial, whose humoral responses against the MSP2-3D7 allele were boosted, were rendered more susceptible than the placebo controls to parasitization with heterologous FC27-type parasites (16,19). Early studies showed that mouse monoclonal antibodies (MAbs) that discriminated between heterologous parasites affected homologous in vitro growth inhibition (7, 13). Curiously, there is scant evidence of the inability of allele-specific MAbs to inhibit heterologous parasites in vitro (45).Like other P. falciparum antigens, MSP2 antibody responses are skewed to cytophilic (IgG1 and IgG3) isotypes (37,43,50,53,54), which have been positively associated with protection from malaria (4,11,21,37,44,50,54). These isotypes bind via their Fc domain to Fc␥ receptors, thereby eliciting cellular immune responses of the innate immune system. Antibody opsonization of P. falciparum-infected erythrocytes and merozoites enhances their phagocytosis (6,12,22,30,3...

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Cross–reactivity of antibody against an epitope of the Plasmodium falciparum second merozoite surface antigen

Cited by 38 publications

References 13 publications

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity.

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

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