Abstract
BackgroundEndothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria. Soluble EPCR (sEPCR) inhibits binding of P. falciparum to EPCR in vitro and increased levels of sEPCR have been associated with the H3 haplotype of the EPCR encoding PROCR gene. It has been hypothesized that elevated sEPCR levels, possibly linked to the PROCR H3 genetic variant, may confer protection against severe forms of malaria. This study determined the frequencies of PROCR haplotypes H1–4 and plasma levels of sEPCR in a Tanzanian study population to investigate a possible association with severe malaria. MethodsStudy participants were children under 5 years of age admitted at the Korogwe District Hospital (N = 143), and diagnosed as having severe malaria (N = 52; including cerebral malaria N = 17), uncomplicated malaria (N = 24), or an infection other than malaria (N = 67). In addition, blood samples from 71 children living in nearby villages were included. The SNPs defining the haplotypes of PROCR gene were determined by post-PCR ligation detection reaction-fluorescent microsphere assay.ResultsIndividuals carrying at least one H3 allele had significantly higher levels of sEPCR than individuals with no H3 alleles (P < 0.001). No difference in the frequency of H3 was found between the non-malaria patients, malaria patients or the village population (P > 0.1). Plasma levels of sEPCR differed between these three groups, with higher sEPCR levels in the village population compared to the hospitalized patients (P < 0.001) and higher levels in malaria patients compared to non-malaria patients (P = 0.001). However, no differences were found in the distribution of H3 (P = 0.2) or levels of sEPCR (P = 0.8) between patients diagnosed with severe and uncomplicated malaria.ConclusionFrequencies of SNPs determining PROCR haplotypes were in concordance with other African studies. The PROCR H3 allele was associated with higher levels of sEPCR, confirming earlier findings, however, in this Tanzanian population; neither PROCR haplotype nor level of sEPCR was associated with severe malaria, however, larger studies are needed to confirm these findings.
Highlights
Endothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria
Determination of haplotype 1–4 (H1–4) PROCR haplotypes The specificity of the ligase detection reaction-fluorescent microsphere assay (LDR-FMA) methodology was confirmed with control DNA samples from individuals with
This study investigated the four defined EPCR haplotypes resulting from single nucleotide polymorphism (SNP) of the PROCR gene and their possible association with the level of Soluble EPCR (sEPCR) and disease outcome in Tanzanian patients infected with falciparum malaria
Summary
Endothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria. Severe and fatal cases of malaria are caused by Plasmodium falciparum infection [2], and this is precipitated by the ability of this parasite to attach infected erythrocytes to the microvasculature This sequestration of parasites causes blood occultation and inflammation in host organs, including the brain. EPCR, known as activated protein C (APC) receptor plays a key role in the regulation of coagulation, inflammation and endothelial cell integrity [5,6,7,8,9]. It is a transmembrane glycoprotein, mainly expressed on endothelial cells, and on a variety of other cells, including neutrophils [10,11,12,13,14]. It is likely that EPCR-mediated parasite sequestration aggravates malaria pathogenesis by disrupting the anti-coagulative, anti-inflammatory and cytoprotective effects of APC [3, 4]
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