Antibodies Targeting the PfRH1 Binding Domain Inhibit Invasion of Plasmodium falciparum Merozoites

Gao, Xiaohong; Yeo, Kim Pin; Aw, Sharon Siqi; Kuss, Claudia; Iyer, Jayasree K.; Genesan, Saraswathy; Rajamanonmani, Ravikumar; Lescar, Julien; Bozdech, Zbynek; Preiser, Peter R.

doi:10.1371/journal.ppat.1000104

Cited by 70 publications

(129 citation statements)

References 66 publications

(129 reference statements)

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“…1B, enzyme treatment of mouse erythrocytes with neuraminidase, trypsin, and chymotrypsin revealed the Py235 receptor to be neuraminidase resistant and trypsin and chymotrypsin sensitive, which is in line with recent data (45). A number of studies have identified the erythrocyte binding regions of two members of the RH family in P. falciparum (19,23). For both PfRH1 and PfRH4, the binding region is located in the N-terminal half of the protein (Fig.…”

Section: Identification Of the Erythrocyte Binding Region Of Py235supporting

confidence: 84%

“…In addition to its role in host cell selection, immune evasion, and virulence during the blood stage of the infection, it is also implicated in playing a role in the sporozoite stage of the infection. Antibodies targeting Py235 of P. yoelii have been shown to successfully protect the host against the virulent strain of this parasite (18,33), and in vitro culture experiments have also demonstrated that antibodies against RH of P. falciparum can inhibit merozoite invasion (5,19,23,63). While the redundancy of this protein family poses a challenge, the available data suggest that one or more RH may be an ideal component of a future vaccine targeting merozoite invasion.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike the case of the EBL, there is no easily identifiable domain structure in RH, making it difficult to identify functional domains within these large proteins. Recently, the erythrocyte binding regions of PfRH1, PfRH4, and PfRH5 of the RH family in P. falciparum have been mapped and have shown limited overall sequence conservation between them (5,19,23,32,50,63). At this stage, no structural information is available for any members of the RH family.…”

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Structural Characterization of the Erythrocyte Binding Domain of the Reticulocyte Binding Protein Homologue Family of Plasmodium yoelii

et al. 2011

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Invasion of the host cell by the malaria parasite is a key step for parasite survival and the only stage of its life cycle where the parasite is extracellular, and it is therefore a target for an antimalaria intervention strategy. Multiple members of the reticulocyte binding protein homologues (RH) family are found in all plasmodia and have been shown to bind to host red blood cells directly. In the study described here, we delineated the erythrocyte binding domain (EBD) of one member of the RH family, termed Py235, from Plasmodium yoelii. Moreover, we have obtained the low-resolution structure of the EBD using small-angle X-ray scattering. Comparison of the EDB structure to other characterized Plasmodium receptor binding domains suggests that there may be an overall structural conservation. These findings may help in developing new approaches to target receptor ligand interactions mediated by parasite proteins.Differences in the ability of the invasive form of the malaria parasite, the merozoite, to recognize and invade red blood cells (RBC) have a direct impact on disease severity. In the case of the human parasite Plasmodium vivax, invasion is restricted to reticulocytes, leading to a lower parasite burden than that of Plasmodium falciparum, which is able to invade RBC of all ages. Differences in the repertoire and expression of parasite ligands on the merozoite are responsible in defining the invasion characteristics of the different parasite species.Two protein families, called erythrocyte binding-like proteins (EBL) and reticulocyte binding protein homologues (RH), are found in all Plasmodium species and have been shown to be key ligands that enable the parasite to recognize different receptors on the RBC surface (reviewed in references 22 and 34). The total number of EBL varies between different parasite species, with P. falciparum having five members while P. vivax has only a single member (1,11,20). All members of the EBL proteins are defined by the presence of the cysteinerich Duffy binding-like (DBL) domain, with each DBL domain mediating binding to a single receptor on the RBC (1, 2, 26, 40-42). Both in P. falciparum and in P. vivax the RBC receptors recognized by the different members of the EBL family are known. The receptor recognized by each EBL directly correlates with the binding specificity of its DBL domain. As with the EBL, the number of RH varies between different parasite species, ranging from as few as 6 members in P. falciparum to as many as 14 in the rodent malaria parasite Plasmodium yoelii (12,13,20). In P. falciparum, different members of the RH are able to recognize different receptors on the RBC, and the combination of RH and EBL expressed in the merozoite defines unique invasion pathways (3, 6-8, 16, 17, 19, 21, 26, 31, 35, 39, 42, 46, 47, 49, 50, 56, 62, 65). Unlike the case of the EBL, there is no easily identifiable domain structure in RH, making it difficult to identify functional domains within these large proteins. Recently, the erythrocyte binding regions of PfRH1, PfRH4, ...

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Section: Identification Of the Erythrocyte Binding Region Of Py235supporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural Characterization of the Erythrocyte Binding Domain of the Reticulocyte Binding Protein Homologue Family of Plasmodium yoelii

et al. 2011

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“…The quality of protein expression and folding had been validated previously for some of the protein constructs used by demonstrating that vaccine-induced Abs raised against the recombinant protein recognize native protein (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37); vaccine-induced Abs have functional antiparasite activity in growthinhibition assays (GIAs) or Ab-dependent cellular-inhibition (ADCI) assays (12,28,30,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43); or the recombinant protein has appropriate biological function by binding its receptor (25,28,34,35,38,39) (Supplemental Table I). Validation of WGCF as an appropriate system for expression of P. falciparum merozoite proteins has also been established in several ways.…”

Section: Expression Of Ragsmentioning

confidence: 99%

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

Richards

Arumugam

Reiling

et al. 2013

The Journal of Immunology

216

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The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control.

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“…experimental animals to PfRh1, PfRh2, PfRh4, and PfRh5 can inhibit invasion (22,(24)(25)(26)(27). Furthermore, genetic disruption of specific members alters the erythrocyte receptor preference of merozoites during invasion (6,13).…”

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Evidence That the Erythrocyte Invasion Ligand PfRh2 is a Target of Protective Immunity against Plasmodium falciparum Malaria

Reiling

Richards

Fowkes

et al. 2010

The Journal of Immunology

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Abs targeting blood-stage Ags of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologs (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight recombinant proteins covering the entire PfRh2 common region, as well as PfRh2a- and PfRh2b-specific regions. Abs were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 mo for reinfection and malaria. At baseline, Abs were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high-density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analyzed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein and seem to be under diversifying selection, suggesting immune pressure. Cluster analysis arranged the sequences into two main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans and that Abs act by controlling blood-stage parasitemia and support its potential for vaccine development.

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Antibodies Targeting the PfRH1 Binding Domain Inhibit Invasion of Plasmodium falciparum Merozoites

Cited by 70 publications

References 66 publications

Structural Characterization of the Erythrocyte Binding Domain of the Reticulocyte Binding Protein Homologue Family of Plasmodium yoelii

Structural Characterization of the Erythrocyte Binding Domain of the Reticulocyte Binding Protein Homologue Family of Plasmodium yoelii

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

Evidence That the Erythrocyte Invasion Ligand PfRh2 is a Target of Protective Immunity against Plasmodium falciparum Malaria

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