scholarly journals Severe malaria is associated with parasite binding to endothelial protein C receptor

Nature ◽  
2013 ◽  
Vol 498 (7455) ◽  
pp. 502-505 ◽  
Author(s):  
Louise Turner ◽  
Thomas Lavstsen ◽  
Sanne S. Berger ◽  
Christian W. Wang ◽  
Jens E. V. Petersen ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Endothelial Protein C Receptor

scholarly journals Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant

2015 ◽  
Vol 114 (11) ◽  
pp. 1038-1048 ◽  
Author(s):  
Eveline A. M. Bouwens ◽  
Ibai Tamayo ◽  
Louise Turner ◽  
Christian W. Wang ◽  
Monique Stins ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Severe Malaria ◽  
Protein C ◽  
Cellular Response ◽  
Malaria Parasite ◽  
Vascular Endothelial Cells ◽  
Protective Effects ◽  
Endothelial Protein C Receptor ◽  
Parasite Protein ◽  
Soluble Epcr

SummaryThe Endothelial Protein C receptor (EPCR) is essential for the anticoagulant and cytoprotective functions of the Protein C (PC) system. Selected variants of the malaria parasite protein, Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) associated with severe malaria, including cerebral malaria, specifically target EPCR on vascular endothelial cells. Here, we examine the cellular response to PfEMP1 engagement to elucidate its role in malaria pathogenesis. Binding of the CIDRα1.1 domain of PfEMP1 to EPCR obstructed activated PC (APC) binding to EPCR and induced a loss of cellular EPCR functions. CIDRα1.1 severely impaired endothelial PC activation and effectively blocked APC-mediated activation of protease-activated receptor-1 (PAR1) and associated barrier protective effects of APC on endothelial cells. A soluble EPCR variant (E86A-sEPCR) bound CIDRα1.1 with high affinity and did not interfere with (A)PC binding to cellular EPCR. E86A-sEPCR used as a decoy to capture PfEMP1, permitted normal PC activation on endothelial cells, normal barrier protective effects of APC, and greatly reduced cytoadhesion of infected erythrocytes to brain endothelial cells. These data imply important contributions of PfEMP1-induced protein C pathway defects in the pathogenesis of severe malaria. Furthermore, the E86A-sEPCR decoy provides a proof-of-principle strategy for the development of novel adjunct therapies for severe malaria.

scholarly journals The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Sixbert I. Mkumbaye ◽  
Christian W. Wang ◽  
Eric Lyimo ◽  
Jakob S. Jespersen ◽  
Alphaxard Manjurano ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Severe Malaria ◽  
Erythrocyte Membrane ◽  
Protein C ◽  
Transcript Level ◽  
Endothelial Protein C Receptor ◽  
Transcript Levels ◽  
Content Type ◽  
Erythrocyte Membrane Protein

ABSTRACT By attaching infected erythrocytes to the vascular lining, Plasmodium falciparum parasites leave blood circulation and avoid splenic clearance. This sequestration is central to pathogenesis. Severe malaria is associated with parasites expressing an antigenically distinct P. falciparum erythrocyte membrane protein 1 (PfEMP1) subset mediating binding to endothelial receptors. Previous studies indicate that PfEMP1 adhesins with so-called CIDRα1 domains capable of binding endothelial protein C receptor (EPCR) constitute the PfEMP1 subset associated with severe pediatric malaria. To analyze the relative importance of different subtypes of CIDRα1 domains, we compared Pfemp1 transcript levels in children with severe malaria (including 9 fatal and 114 surviving cases), children hospitalized with uncomplicated malaria (n = 42), children with mild malaria not requiring hospitalization (n = 10), and children with parasitemia and no ongoing fever (n = 12). High levels of transcripts encoding EPCR-binding PfEMP1 were found in patients with symptomatic infections, and the abundance of these transcripts increased with disease severity. The compositions of CIDRα1 subtype transcripts varied markedly between patients, and none of the subtypes were dominant. Transcript-level analyses targeting other domain types indicated that subtypes of DBLβ or DBLζ domains might mediate binding phenomena that, in conjunction with EPCR binding, could contribute to pathogenesis. These observations strengthen the rationale for targeting the PfEMP1-EPCR interaction by vaccines and adjunctive therapies. Interventions should target EPCR binding of all CIDRα1 subtypes.

scholarly journals The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Estela Shabani ◽  
Robert O. Opoka ◽  
Paul Bangirana ◽  
Gregory S. Park ◽  
Gregory M. Vercellotti ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Endothelial Protein C Receptor ◽  
Soluble Epcr

scholarly journals A meta-analysis of the endothelial protein C receptor rs867186 genotype in malaria

2019 ◽  
Author(s):  
Lin Yang ◽  
Ruilian Xin ◽  
Shanchun Guo ◽  
Mingli Liu
Keyword(s):  
Endothelial Cells ◽  
Severe Malaria ◽  
Protein C ◽  
Meta Analysis ◽  
Intercellular Adhesion Molecule ◽  
Healthy Individuals ◽  
Endothelial Protein C Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Soluble Epcr ◽  
Malaria Severity

Abstract BACKGROUND : During P. falciparum infection, the binding of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to endothelial cells (EC) results in the sequestration of pRBC. Several receptors located on the endothelial cells, including intercellular adhesion molecule 1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR), contribute to PfEMP1 adhesion to the microvasculature. PfEMP1, expressed on the surface of parasitized red blood cells (pRBC), is composed of cysteine-rich interdomain regions (CIDR) and Duffy binding-like (DBL) domains. CIDRα1 competitively binds to EPCR with activated protein C (APC) and impairs cytoprotective and anticoagulant effects by APC, which plays important roles in severe malaria (SM) pathogenesis such as cerebral malaria (CM) and severe malaria anemia (SMA). The strategy to inhibit EPCR binding to pRBC while concomitantly strengthen its binding to APC may be crucial in restoring disrupted protein C (PC) system’s function. The purpose of this study is to evaluate the association between malaria severity and the EPCR genotypes as well as with soluble EPCR (sEPCR), and the study also addresses the physiological relevance of EPCR genetic polymorphism. RESULTS : In this study, we conducted a meta-analysis on the eligible studies by comparing the frequency of EPCR rs867186-GG versus rs867186-GA and -AA genotype in SM, mild malaria (MM) or uncomplicated malaria (UM) patients and healthy individuals from Thailand, Uganda, Benin, Tanzania, and Ghana. We also determined the relationship between rs867186 genotype and sEPCR levels. Our results showed that the genotype rs867186-GG is higher in MM/UM than in SM patients. SM patients carrying the rs867186-GG genotype have higher plasma soluble EPCR (sEPCR) levels than in rs867186-AG and rs867186-AA carriers. MM/UM patients carrying the rs867186-AG genotype have significantly higher level of sEPCR compared to those carrying rs867186-AA. Similarly, the rs867186-GG is associated with high sEPCR level in healthy individuals. CONCLUSIONS : This meta-analysis demonstrates that pRBCs and EPCR interactions are associated with malaria severity, and treatments that block their binding via PfEMP1 CIDRα1 could be a potential therapy for SM.

scholarly journals Association of the endothelial protein C receptor (PROCR) rs867186-G allele with protection from severe malaria

2014 ◽  
Vol 13 (1) ◽  
pp. 105 ◽  
Author(s):  
Izumi Naka ◽  
Jintana Patarapotikul ◽  
Hathairad Hananantachai ◽  
Hiroo Imai ◽  
Jun Ohashi
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Endothelial Protein C Receptor

scholarly journals Haplotypes of the endothelial protein C receptor (EPCR) gene are not associated with severe malaria in Tanzania

2015 ◽  
Vol 14 (1) ◽  
Author(s):  
Helle Holm Hansson ◽  
Louise Turner ◽  
Line Møller ◽  
Christian William Wang ◽  
Daniel T. R. Minja ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Endothelial Protein C Receptor

scholarly journals Endothelial Protein C Receptor Gene Variants Not Associated with Severe Malaria in Ghanaian Children

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e115770 ◽  
Author(s):  
Kathrin Schuldt ◽  
Christa Ehmen ◽  
Jennifer Evans ◽  
Juergen May ◽  
Daniel Ansong ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Receptor Gene ◽  
Gene Variants ◽  
Endothelial Protein C Receptor

scholarly journals IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

2015 ◽  
Vol 83 (8) ◽  
pp. 3096-3103 ◽  
Author(s):  
Louise Turner ◽  
Thomas Lavstsen ◽  
Bruno P. Mmbando ◽  
Christian W. Wang ◽  
Pamela A. Magistrado ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Malaria Transmission ◽  
Severe Malaria ◽  
Erythrocyte Membrane ◽  
Protein C ◽  
Endothelial Protein C Receptor ◽  
Content Type ◽  
Erythrocyte Membrane Protein ◽  
Amino Terminal

Severe malaria syndromes are precipitated byPlasmodium falciparumparasites binding to endothelial receptors on the vascular lining. This binding is mediated by members of the highly variantP. falciparumerythrocyte membrane protein 1 (PfEMP1) family. We have previously identified a subset of PfEMP1 proteins associated with severe malaria and found that the receptor for these PfEMP1 variants is endothelial protein C receptor (EPCR). The binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDR) of the subtypes α1.1 and α1.4 to α1.8. In this study, we investigated the acquisition of anti-CIDR antibodies using plasma samples collected in four study villages with different malaria transmission intensities in northeastern Tanzania during a period with a decline in malaria transmission. We show that individuals exposed to high levels of malaria transmission acquire antibodies to EPCR-binding CIDR domains early in life and that these antibodies are acquired more rapidly than antibodies to other CIDR domains. The rate by which antibodies to EPCR-binding CIDR domains are acquired in populations in areas where malaria is endemic is determined by the malaria transmission intensity, and on a population level, the antibodies are rapidly lost if transmission is interrupted. This indicates that sustained exposure is required to maintain the production of the antibodies.

scholarly journals Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

2016 ◽  
Vol 113 (23) ◽  
pp. E3270-E3279 ◽  
Author(s):  
Maria Bernabeu ◽  
Samuel A. Danziger ◽  
Marion Avril ◽  
Marina Vaz ◽  
Prasad H. Babar ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Protein C ◽  
Adult Population ◽  
Activated Protein C ◽  
Brain Endothelial Cells ◽  
Endothelial Protein C Receptor ◽  
Molecular Determinants ◽  
Infected Adult ◽  
Learning Analysis ◽  
High Parasite

The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6- and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence.

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