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 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 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):  
Severe Malaria ◽  
Protein C ◽  
Meta Analysis ◽  
Activated Protein C ◽  
Intercellular Adhesion Molecule ◽  
Healthy Individuals ◽  
Endothelial Protein C Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Significant Difference ◽  
Soluble Epcr

Abstract The interaction between the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of parasitized red blood cells (pRBC) and the endothelial cells (EC) receptors during P. falciparum infection results in the sequestration of pRBC from blood circulation. The amount of sequestration is determined by specific interactions among PfEMP1 and several host adhesion receptors, including intercellular adhesion molecule 1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR). PfEMP1 is composed of multiple domains such as the cysteine-rich inter domain region (CIDR) and Duffy binding –like (DBL) domains. CIDRα1 competitively binds to EPCR with activated protein C (APC) and impair cytoprotective and anticoagulant effects by APC, which plays an important role in severe malaria (SM) pathogenesis such as cerebral malaria (CM) and severe malaria anemia (SMA). The strategy to inhibit EPCR binding to pRBC while to concomitantly strengthen its binding to APC may be crucial in restoring impaired protein C (PC) system’s function. The purpose of this study is to evaluate the association between severity of malaria and the EPCR genotypes as well as the soluble EPCR (sEPCR), and the study also addresses the physiological relevance of EPCR genetic polymorphism. In this study, we conducted 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 gene type of 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. A significant difference is seen with the higher plasma sEPCR expression among MM/UM patients carrying the rs867186-AG genotype compared to those carrying rs867186-AA. Similarly, the rs867186-GG is associated with sEPCR level in healthy individuals. In conclusion, this meta-analysis demonstrates that pRBCs and EPCR interactions are associated with malaria severity, and treatments that block pRBC binding to EPCR via PfEMP1 CIDRα1 could be a potential therapy for SM.

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 Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum -Infected Erythrocytes to Endothelial Cells

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Marion Avril ◽  
Maria Bernabeu ◽  
Maxwell Benjamin ◽  
Andrew Jay Brazier ◽  
Joseph D. Smith
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Intercellular Adhesion Molecule ◽  
Brain Endothelial Cells ◽  
Endothelial Protein C Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Cd36 Expression ◽  
Tnf Α ◽  
Group A ◽  
The Brain

ABSTRACT Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria. However, it remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. Here, we investigated this issue by studying different subtypes of ICAM-1-binding parasite lines. We show that two parasite lines expressing domain cassette 13 (DC13) of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family have dual binding specificity for EPCR and ICAM-1 and further mapped ICAM-1 binding to the first DBLβ domain following the PfEMP1 head structure in both proteins. As PfEMP1 head structures have diverged between group A (EPCR binders) and groups B and C (CD36 binders), we also investigated how ICAM-1-binding parasites with different coreceptor binding traits influence P. falciparum -infected erythrocyte binding to endothelial cells. Whereas levels of binding to tumor necrosis factor alpha (TNF-α)-stimulated endothelial cells from the lung and brain by all ICAM-1-binding parasite lines increased, group A (EPCR and ICAM-1) was less dependent than group B (CD36 and ICAM-1) on ICAM-1 upregulation. Furthermore, both group A DC13 parasite lines had higher binding levels to brain endothelial cells (a microvascular niche with limited CD36 expression). This study shows that ICAM-1 is a coreceptor for a subset of EPCR-binding parasites and provides the first evidence of how EPCR and ICAM-1 interact to mediate parasite binding to both resting and TNF-α-activated primary brain and lung endothelial cells. IMPORTANCE Cerebral malaria is a severe neurological complication of P. falciparum infection associated with infected erythrocyte (IE) binding in cerebral vessels. Yet little is known about the mechanisms by which parasites adhere in the brain or other microvascular sites. Here, we studied parasite lines expressing group A DC13-containing PfEMP1 variants, a subset that has previously been shown to have high brain cell- and other endothelial cell-binding activities. We show that DC13-containing PfEMP1 variants have dual EPCR- and ICAM-1-binding activities and that both receptors are involved in parasite adherence to lung and brain endothelial cells. As both EPCR and ICAM-1 are implicated in cerebral malaria, these findings suggest the possibility that parasites with dual binding activities are involved in parasite sequestration to microvascular beds with low CD36 expression, such as the brain, and we urge more research into the multiadhesive properties of PfEMP1 variants.

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 HDL-Mediated Lipid Influx to Endothelial Cells Contributes to Regulating Intercellular Adhesion Molecule (ICAM)-1 Expression and eNOS Phosphorylation

2018 ◽  
Vol 19 (11) ◽  
pp. 3394 ◽  
Author(s):  
Mónica Muñoz-Vega ◽  
Felipe Massó ◽  
Araceli Páez ◽  
Gilberto Vargas-Alarcón ◽  
Ramón Coral-Vázquez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Hdl Cholesterol ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
High Density Lipoproteins ◽  
Type I ◽  
Intercellular Adhesion Molecule 1 ◽  
Apo Ai

Reverse cholesterol transport (RCT) is considered as the most important antiatherogenic role of high-density lipoproteins (HDL), but interventions based on RCT have failed to reduce the risk of coronary heart disease. In contrast to RCT, important evidence suggests that HDL deliver lipids to peripheral cells. Therefore, in this paper, we investigated whether HDL could improve endothelial function by delivering lipids to the cells. Internalization kinetics using cholesterol and apolipoprotein (apo) AI fluorescent double-labeled reconstituted HDL (rHDL), and human dermal microvascular endothelial cells-1 (HMEC-1) showed a fast cholesterol influx (10 min) and a slower HDL protein internalization as determined by confocal microscopy and flow cytometry. Sphingomyelin kinetics overlapped that of apo AI, indicating that only cholesterol became dissociated from rHDL during internalization. rHDL apo AI internalization was scavenger receptor class B type I (SR-BI)-dependent, whereas HDL cholesterol influx was independent of SR-BI and was not completely inhibited by the presence of low-density lipoproteins (LDL). HDL sphingomyelin was fundamental for intercellular adhesion molecule-1 (ICAM-1) downregulation in HMEC-1. However, vascular cell adhesion protein-1 (VCAM-1) was not inhibited by rHDL, suggesting that components such as apolipoproteins other than apo AI participate in HDL’s regulation of this adhesion molecule. rHDL also induced endothelial nitric oxide synthase eNOS S1177 phosphorylation in HMEC-1 but only when the particle contained sphingomyelin. In conclusion, the internalization of HDL implies the dissociation of lipoprotein components and a SR-BI-independent fast delivery of cholesterol to endothelial cells. HDL internalization had functional implications that were mainly dependent on sphingomyelin. These results suggest a new role of HDL as lipid vectors to the cells, which could be congruent with the antiatherogenic properties of these lipoproteins.

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