The Merozoite Surface Protein 1 Complex Is a Platform for Binding to Human Erythrocytes by Plasmodium falciparum

Lin, Clara S.; Uboldi, Alessandro D.; Marapana, Danushka S.; Czabotar, P.E.; Epp, Christian; Bujard, Hermann; Taylor, Nicole; Perugini, Matthew A.; Hodder, Anthony N.; Cowman, Alan F.

doi:10.1074/jbc.m114.586495

Cited by 50 publications

(63 citation statements)

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“…47 However, this study did not detect a direct interaction of MSP1 with human RBCs. In our view, this discrepancy could originate from the protein preparations used in that study.…”

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confidence: 71%

“…A full-length recombinant MSP1 assembled by tandem tethering of respective MSP1 fragments was used for the RBC binding assays. 47 Due to the poor solubility, recombinant full-length MSP1 was subjected to denaturation and renaturation steps, likely resulting in the loss of conformational folding and protein-binding activity. In our experience, recombinant MSP1 is best expressed as soluble subdomains without subjecting them to denaturation-renaturation steps (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Baldwin

Hanada

et al. 2015

Blood

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• The N-terminal subunit of MSP1 binds to a specific polypeptide region of GPA during merozoite invasion of human RBCs.• The GPA-band 3 complex plays an essential role during malaria parasite invasion.Plasmodium falciparum invasion of human red blood cells (RBCs) is an intricate process requiring a number of distinct ligand-receptor interactions at the merozoite-erythrocyte interface. Merozoite surface protein 1 (MSP1), a highly abundant ligand coating the merozoite surface in all species of malaria parasites, is essential for RBC invasion and considered a leading candidate for inclusion in a multiple-subunit vaccine against malaria. Our previous studies identified an interaction between the carboxyl-terminus of MSP1 and RBC band 3. Here, by employing phage display technology, we report a novel interaction between the amino-terminus of MSP1 and RBC glycophorin A (GPA). Mapping of the binding domains established a direct interaction between malaria MSP1 and human GPA within a region of MSP1 known to potently inhibit P falciparum invasion of human RBCs. Furthermore, a genetically modified mouse model lacking the GPA-band 3 complex in RBCs is completely resistant to malaria infection in vivo. These findings suggest an essential role of the MSP1-GPA-band 3 complex during the initial adhesion phase of malaria parasite invasion of RBCs. (Blood. 2015;125(17):2704-2711 IntroductionMalaria remains one of the most common and deadly parasitic diseases in the world. The World Health Organization estimates that 5% to 9% of the global population is infected by malaria annually, resulting in over 700 000 deaths.1 Children younger than 5 years are most vulnerable to Plasmodium falciparum, the most lethal species among 4 malaria parasites that commonly infect humans. Malaria also takes an enormous economic toll by impacting the economies of most endemic countries, particularly in sub-Saharan Africa. Historically, vaccines have been one of the most effective means of controlling infectious diseases. Accumulating evidence suggests that a malaria vaccine can be developed 2,3 ; however, most malaria vaccine candidate antigens have suffered limitations of low immunogenicity and efficacy. To date, no licensed vaccine exists for malaria despite the urgent global need.Clinical manifestation and mortality in malaria is directly associated with the blood stage of the parasite life cycle. The invasion process consists of multiple molecular events during which red blood cell (RBC) membrane proteins and merozoite-coat proteins are engaged in specific receptor-ligand interactions to form unique invasion pathways. 4,5 Continued interest in developing a multiantigen malaria vaccine has drawn much attention to parasite proteins localized on the surface and at the apical end of the merozoite as potential vaccine candidates. 4 Merozoite surface protein 1 (MSP1) is a major ligand coating the surface of merozoites in all species of malaria parasites 6 and is considered one of the leading candidates for inclusion in a multiplesubunit vaccine against...

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“…47 However, this study did not detect a direct interaction of MSP1 with human RBCs. In our view, this discrepancy could originate from the protein preparations used in that study.…”

contrasting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Baldwin

Hanada

et al. 2015

Blood

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“…3D7, D10, K1, HB3, E8B, Palo Alto, and W2MEF strains were cultured as described previously (21). The D10PfMSP1-19 and D10PcMSP1-19 lines (where Pf is P. falciparum and Pc is Plasmodium chabaudi, respectively) were maintained with 24 ng/ml pyrimethamine (22), and 3D7⌬MSP3, 3D7⌬MSP6, and 3D7⌬MSPDBL1 lines were generated by transfection with constructs assembled in pCC1 (23). The PNG strain XHA_A has been reported previously (24), whereas all other PNG strains were adapted from erythrocytes cryopreserved in Glycerolyte 57 (Fenwal) from high-parasitemia baseline blood samples.…”

Section: Methodsmentioning

confidence: 99%

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

et al. 2016

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h It is unclear whether naturally acquired immunity to Plasmodium falciparum results from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasmamatched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or P. falciparum MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.

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“…The remaining ectodomain of MSP1 is shed into the bloodstream following invasion (8 -12). Other peripheral MSPs, such as MSP3, MSP6, MSP-DBL1, MSPDBL2, and MSP7, interact directly with MSP1 on the surface of parasites and are also shed following invasion (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

“…The peripheral proteins MSPDBL1 and MSPDBL2 bind to MSP1 on the parasite surface and facilitate binding to red blood cells (17)(18)(19). In a study utilizing peptide fragments for MSP3, synthetic MSP3 peptides were shown to have some involvement in binding to host erythrocytes (20).…”

mentioning

confidence: 99%

Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes

Lin

Uboldi

Epp

et al. 2016

Journal of Biological Chemistry

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Successful invasion of human erythrocytes by Plasmodium falciparum merozoites is required for infection of the host and parasite survival. The early stages of invasion are mediated via merozoite surface proteins that interact with human erythrocytes. The nature of these interactions are currently not well understood, but it is known that merozoite surface protein 1 (MSP1) is critical for successful erythrocyte invasion. Here we show that the peripheral merozoite surface proteins MSP3, MSP6, MSPDBL1, MSPDBL2, and MSP7 bind directly to MSP1, but independently of each other, to form multiple forms of the MSP1 complex on the parasite surface. These complexes have overlapping functions that interact directly with human erythrocytes. We also show that targeting the p83 fragment of MSP1 using inhibitory antibodies inhibits all forms of MSP1 complexes and disrupts parasite growth in vitro.

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The Merozoite Surface Protein 1 Complex Is a Platform for Binding to Human Erythrocytes by Plasmodium falciparum

Cited by 50 publications

References 51 publications

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes

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