Parasites Causing Cerebral Falciparum Malaria Bind Multiple Endothelial Receptors and Express EPCR and ICAM-1-Binding PfEMP1

Ndam, Nicaise Tuikue; Moussiliou, Azizath; Lavstsen, Thomas; Kamaliddin, Claire; Jensen, Anja T. R.; Mama, Atikatou; Tahar, Rachida; Wang, Christian W.; Jespersen, Jakob S.; Alao, Jules; Gamain, B; Theander, Thor G.; Deloron, Philippe

doi:10.1093/infdis/jix230

Cited by 71 publications

(58 citation statements)

References 33 publications

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“…The CIDR␣1-mediated attachment of infected erythrocytes to EPCR is a potential target for vaccines to prevent severe malaria. Characterization of PfEMP1 expressed in severe malaria indicates that all EPCR-binding CIDR␣1 subtypes can precipitate disease (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Thus, an effective malaria vaccine targeting PfEMP1 probably has to target most, if not all, CIDR␣1 subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…A large body of immunoepidemiological evidence (recently reviewed in Bull and Abdi [10]) has converged on a subset of PfEMP1 molecules being the main target of IgG protecting against severe malaria. Recent studies of PfEMP1 gene expression in patients have identified the subset of PfEMP1 molecules associated with development of severe malaria symptoms, including severe anemia and cerebral malaria (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). This subset is defined by carrying a so-called CIDR␣1 domain mediating tethering to endothelial cells through binding to endothelial protein C receptor (EPCR) (22).…”

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Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

2018

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malaria pathogenesis is tied to the sequestration of parasites in the microvasculature. Parasite sequestration leading to severe malaria is mediated by erythrocyte membrane protein 1 (PfEMP1) binding to endothelial protein C receptor (EPCR) via its CIDRα1 domains. CIDRα1 domains are targets of naturally acquired immunity, and a vaccine eliciting antibodies inhibiting the EPCR binding of CIDRα1 could potentially prevent disease and death from malaria. CIDRα1 domains have diversified in sequence to escape immune recognition but preserved structure to maintain EPCR binding. The EPCR-binding CIDRα1 domains separate into six major sequence types predicted to form a conserved structure in which only the amino acids essential for EPCR binding are highly conserved. Here, we investigated whether antibodies elicited by vaccination with single or multiple recombinant CIDRα1 domains are able to bind and inhibit diverse CIDRα1 domains. We found that EPCR binding-inhibitory antibodies to CIDRα1 variants closely related to those used for vaccination are readily elicited, whereas antibodies binding distant CIDRα1 variants are sporadically generated and are rarely inhibitory. Despite this, sequence similarity correlated poorly with the ability of induced antibodies to inhibit across diverse variants, and no continuous sequence regions of importance for cross-inhibitory antibodies could be identified. This suggested that epitopes of cross-variant inhibitory antibodies were predominantly conformational. Vaccination with immunogens engineered to focus immune responses to specific epitopes or an optimal choice of multiple CIDRα1 variants may improve elicitation of broadly reactive and inhibitory antibody responses.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

2018

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“…More recently parasites causing cerebral malaria were shown to express var genes encoding for PfEMP1s that bind EPCR and ICAM‐1 in static binding assays (Tuikue Ndam et al , ). Parasites from children with cerebral or uncomplicated malaria were characterized in their transcribed var gene and the binding properties of iRBC collected on admission.…”

Section: Binding Properties Of Different Plasmodium Falciparum Clinicmentioning

confidence: 99%

“…And, when the binding capacity to CD36, ICAM‐1 or EPCR was investigated, adhesion to EPCR and ICAM‐1 was more common in cerebral malaria‐causing parasites than in uncomplicated malaria‐causing parasites. Furthermore, parasite isolates from cerebral malaria patients more frequently exhibited binding to both ICAM‐1 and EPCR, whereas binding to CD36 was more frequent in uncomplicated malaria than cerebral malaria patients (Tuikue Ndam et al , ).…”

Section: Binding Properties Of Different Plasmodium Falciparum Clinicmentioning

confidence: 99%

Binding brain better—matching var genes and endothelial receptors

Fleckenstein

Portugal

2019

EMBO Mol Med

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Cerebral malaria remains a major cause of death for African children, and mechanistic insights regarding the establishment of brain pathology are greatly needed. Expression of specific domains of parasite's var genes promoting brain adhesion of infected erythrocytes had been previously identified, but binding specificities and the receptor preference in the brain endothelial cells had not been fully described. The study by Storm et al () in this issue of EMBO Molecular Medicine demonstrates that binding to brain endothelial cells via EPCR and ICAM‐1 is increased in parasites causing cerebral malaria compared to parasites causing uncomplicated malaria. Furthermore, expression levels of var genes encoding the CIDRα1 domain with EPCR affinity correlate with the receptor‐dependent binding to brain, but not dermal endothelial cells, highlighting the important role of EPCR in cerebral malaria pathology.

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“…A particular association with cerebral symptoms was found for parasites expressing PfEMP1s that combine both an EPCR-binding CIDRα1 domain and a DBLβ domain that can bind to ICAM-1, allowing simultaneous binding of infected erythrocytes to both ligands [38,42,43] (Figure 1). (A) The architecture of PfEMP1 ectodomains displayed on the surface of erythrocytes infected with P. falciparum.…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Towards an anti-disease malaria vaccine

Lennartz

Lavstsen

Higgins

2017

Emerging Topics in Life Sciences

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Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

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Parasites Causing Cerebral Falciparum Malaria Bind Multiple Endothelial Receptors and Express EPCR and ICAM-1-Binding PfEMP1

Abstract: These results underpin the significance of EPCR binding in pediatric malaria patients that require hospital admission, and support the notion that complementary receptor interactions of EPCR binding PfEMP1with ICAM-1 amplifies development of severe malaria symptoms.

Cited by 71 publications

References 33 publications

Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

Binding brain better—matching var genes and endothelial receptors

Towards an anti-disease malaria vaccine

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