Characterization of Inhibitors and Monoclonal Antibodies That Modulate the Interaction between Plasmodium falciparum Adhesin PfRh4 with Its Erythrocyte Receptor Complement Receptor 1

Lim, Nicholas; Harder, Markus J.; Kennedy, Alexander T.; Lin, Clara S.; Weir, Christopher; Cowman, Alan F.; Call, Melissa; Schmidt, Christoph Q.; Tham, Wai‐Hong

doi:10.1074/jbc.m115.657171

Cited by 14 publications

(10 citation statements)

References 41 publications

(63 reference statements)

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“…Recent insights again come from malaria parasites, with P. falciparum merozoites exploiting CR1 as an entry receptor . It is particularly interesting that the binding of the responsible malaria adhesin PfRh4 to the N‐terminus of CR1 with nanomolar affinity blocks the DAA of CR1 . Whether this functional impairment of DAA is merely a side effect of merozoite adhesion or may actually enhance the invasion pathway through “voluntary opsonization,” a strategy previously reported for other pathogens, remains to be elucidated.…”

Section: Interplay Between Pathogens and Complement Regulatorsmentioning

confidence: 96%

“…Recent insights again come from malaria parasites, with P. falciparum merozoites exploiting CR1 as an entry receptor 142,143. It is particularly interesting that the binding of the responsible malaria adhesin PfRh4 to the N-terminus of CR1 with nanomolar affinity144,145 blocks the DAA of CR1 62. Whether this functional impairment of DAA is merely a side effect of merozoite adhesion or may actually enhance the invasion pathway through "voluntary opsonization," a strategy previously reported for other pathogens, remains to be elucidated.However, taking into account the fact that merozoites recruit FH to impair complement, the concept of voluntary opsonization seems less likely, yet the decoration of merozoites with iC3b may serve to enhance its interaction with erythrocytes by binding to CR1.…”

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confidence: 99%

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Protection of host cells by complement regulators

Schmidt

Lambris

Ricklin

2016

Immunological Reviews

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177

168

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Summary The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted.

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Section: Interplay Between Pathogens and Complement Regulatorsmentioning

confidence: 96%

mentioning

confidence: 99%

Protection of host cells by complement regulators

Schmidt

Lambris

Ricklin

2016

Immunological Reviews

Self Cite

177

168

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“…In addition to its role in rosetting, CR1 has also been identified as a sialic acid-independent invasion receptor for P. falciparum 47 , via the reticulocyte-binding–like homolog 4 (PfRh4) 48 . The binding of PfRh4 has been mapped to site 1 in LHR-A 49 – 51 . Immuno-fluorescent staining of freshly released invasive merozoites showed CR1 on erythrocytes to be more intense around the merozoite, referred to by the authors as “capping,” suggesting CR1 clustering may have a role in invasion 47 .…”

Section: Discussionmentioning

confidence: 99%

No Evidence that Knops Blood Group Polymorphisms Affect Complement Receptor 1 Clustering on Erythrocytes

Swann

Harrison

Opi

et al. 2017

Sci Rep

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Clustering of Complement Receptor 1 (CR1) in the erythrocyte membrane is important for immune-complex transfer and clearance. CR1 contains the Knops blood group antigens, including the antithetical pairs Swain-Langley 1 and 2 (Sl1 and Sl2) and McCoy a and b (McCa and McCb), whose functional effects are unknown. We tested the hypothesis that the Sl and McC polymorphisms might influence CR1 clustering on erythrocyte membranes. Blood samples from 125 healthy Kenyan children were analysed by immunofluorescence and confocal microscopy to determine CR1 cluster number and volume. In agreement with previous reports, CR1 cluster number and volume were positively associated with CR1 copy number (mean number of CR1 molecules per erythrocyte). Individuals with the McC b /McC b genotype had more clusters per cell than McC a/McC a individuals. However, this association was lost when the strong effect of CR1 copy number was included in the model. No association was observed between Sl genotype, sickle cell genotype, α+thalassaemia genotype, gender or age and CR1 cluster number or volume. Therefore, after correction for CR1 copy number, the Sl and McCoy polymorphisms did not influence erythrocyte CR1 clustering, and the effects of the Knops polymorphisms on CR1 function remains unknown.

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“…Parts of PfRH1 have been shown to be carried into the invaded RBC while some is shed into media upon invasion . Importantly, antibodies targeting RH1, RH2a, RH4 and RH5 have been shown to block merozoite invasion Douglas et al, 2011Douglas et al, , 2014Gunalan et al, 2011Gunalan et al, , 2013Gao et al, 2013;Lim et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

PfRH2b specific monoclonal antibodies inhibit merozoite invasion

Aniweh

Gao

Gunalan

et al. 2016

Molecular Microbiology

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Erythrocyte invasion by merozoite is a multistep process involving multiple ligand-receptor interactions. The Plasmodium falciparum reticulocyte binding protein homologues (PfRHs) consists of five functional members. The differential expression of PfRHs has been linked to the utilization of different invasion pathways by the merozoites as well as a mechanism of immune evasion. PfRHs are expressed at the apical end of merozoite and form interactions with distinct red blood cell (RBC) surface receptors that are important for successful invasion. Here we show that PfRH2b undergoes processing before and during merozoite invasion. The different processed fragments bind to chymotrypsin sensitive RBC surface receptors. We also show that PfRH2b follows the merozoite tight junction during invasion. Monoclonal antibodies (mAbs) inhibit merozoites invasion by blocking tight junction formation. mAbs binding to PfRH2b block merozoites intracellular Ca signal necessary for EBA175 surface expression. The data suggests that a conserved function of PfRHs, where their interaction with RBC surface receptors facilitated recruitment of EBA175 and other tight junction proteins necessary for merozoite invasion by modulating merozoite intracellular Ca signals.

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Characterization of Inhibitors and Monoclonal Antibodies That Modulate the Interaction between Plasmodium falciparum Adhesin PfRh4 with Its Erythrocyte Receptor Complement Receptor 1

Cited by 14 publications

References 41 publications

Protection of host cells by complement regulators

Protection of host cells by complement regulators

No Evidence that Knops Blood Group Polymorphisms Affect Complement Receptor 1 Clustering on Erythrocytes

PfRH2b specific monoclonal antibodies inhibit merozoite invasion

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