Dataset Information

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.

ABSTRACT: Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDR?1.7 domains. Furthermore, a recombinant CIDR?1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDR?1 domains in brain swelling.

SUBMITTER: Kessler A

PROVIDER: S-EPMC5783720 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.

Kessler Anne A Dankwa Selasi S Bernabeu Maria M Harawa Visopo V Danziger Samuel A SA Duffy Fergal F Kampondeni Sam D SD Potchen Michael J MJ Dambrauskas Nicholas N Vigdorovich Vladimir V Oliver Brian G BG Hochman Sarah E SE Mowrey Wenzhu B WB MacCormick Ian J C IJC Mandala Wilson L WL Rogerson Stephen J SJ Sather D Noah DN Aitchison John D JD Taylor Terrie E TE Seydel Karl B KB Smith Joseph D JD Kim Kami K

Cell host & microbe 20171026 5

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are st ...[more]

PMID: 29107642

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Project description:Malaria is still one of the most prevalent infectious diseases in the world. Sequestration of infected erythrocytes (IEs) is the prime mediator of disease. Cytoadhesion of IEs is mediated by members of the highly diverse Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). A restricted sub-set of var genes encoding for PfEMP1s possessing the domain cassettes DC8 and DC13 were found to bind to the endothelial protein C receptor (EPCR). These var genes were shown to be highly expressed by parasites from patients with severe malaria clinical outcomes compared to those from patients with uncomplicated symptoms.In order to further study the molecular mechanisms underlying DC8/DC13 expressing IEs adhesion to EPCR, a method was developed to produce highly pure recombinant EPCR. The IT4 parasite strain was selected on either anti-IT4-VAR19 purified IgG, EPCR or human brain endothelial cell line and their var gene expression profiles as well as their binding phenotypes were compared. The N-terminal region of IT4-VAR19 comprising a full-length DC8 cassette as well as the single EPCR binding CIDR?1.1 domain were also produced, and their immune recognition (IgG) was assessed using plasma samples from Beninese children presenting acute mild malaria, severe malaria or cerebral malaria at the time of their admission to the clinic, and from convalescent-phase plasma collected 30 days after anti-malarial treatment.The multi-domain VAR19-NTS-DBL?6 binds to EPCR with a greater affinity than the CIDR?1.1 domain alone and this study also demonstrates that VAR19-NTS-DBL?6 binding to the EPCR-expressing endothelial cell line (HBEC5i) is more pronounced than that of the CIDR?1.1 domain alone. IT4-VAR19 represents the preferentially expressed-PfEMP1 when FCR3-IEs are selected based on their capability to bind EPCR. Notably, no significant difference in the levels of antibodies towards IT4-VAR19 antigens was observed within all clinical groups between plasma samples collected during the acute malaria phase compared to samples collected 30 days after anti-malaria treatment.These data indicate that even being the preferentially selected IT4-EPCR-binding variant, the IT4-VAR19-DC8 region does not appear to be associated with the acquisition of antibodies during a single severe paediatric malaria episode in Benin.

Dataset Information

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.

Publications

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.

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