The Effect of Anti-Rosetting Agents against Malaria Parasites under Physiological Flow Conditions

Adams, Yvonne; Rowe, J. Alexandra

doi:10.1371/journal.pone.0073999

Cited by 12 publications

(15 citation statements)

References 46 publications

(72 reference statements)

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“…How heparin sulfate-like substance including sevuparin can inhibit or reverse these binding properties, remains to be fully elucidated. Heparan sulfate, and HS-like GAG, expressed on uninfected RBCs are receptors for rosetting [ 17 , 60 , 61 ]. Sevuparin might act as a decoy receptor for CD36, thus causing binding to the drug rather than to the endothelial receptor.…”

Section: Discussionmentioning

confidence: 99%

Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes

et al. 2017

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In severe falciparum malaria cytoadherence of parasitised red blood cells (PRBCs) to vascular endothelium (causing sequestration) and to uninfected red cells (causing rosette formation) contribute to microcirculatory flow obstruction in vital organs. Heparin can reverse the underlying ligand-receptor interactions, but may increase the bleeding risks. As a heparin-derived polysaccharide, sevuparin has been designed to retain anti-adhesive properties, while the antithrombin-binding domains have been eliminated, substantially diminishing its anticoagulant activity. Sevuparin has been evaluated recently in patients with uncomplicated falciparum malaria, and is currently investigated in a clinical trial for sickle cell disease. The effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum isolates from Thailand were investigated. Trophozoite stages of P. falciparum-infected RBCs (Pf-iRBCs) were cultured from 49 patients with malaria. Pf-iRBCs were treated with sevuparin at 37°C and assessed in rosetting and in cytoadhesion assays with human dermal microvascular endothelial cells (HDMECs) under static and flow conditions. The proportion of Pf-iRBCs forming rosettes ranged from 6.5% to 26.0% (median = 12.2%). Rosetting was dose dependently disrupted by sevuparin (50% disruption by 250 μg/mL). Overall 57% of P. falciparum isolates bound to HDMECs under static conditions; median (interquartile range) Pf-iRBC binding was 8.5 (3.0–38.0) Pf-iRBCs/1000 HDMECs. Sevuparin in concentrations ≥ 100 μg/mL inhibited cytoadherence. Sevuparin disrupts P. falciparum rosette formation in a dose dependent manner and inhibits cytoadherence to endothelial cells. The data support assessment of sevuparin as an adjunctive treatment to the standard therapy in severe falciparum malaria.

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Section: Discussionmentioning

confidence: 99%

Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes

et al. 2017

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“…Cells were then subjected for 4 hours to flow conditions using a peristaltic minipump (Thermo Fisher Scientific). The flow was adjusted to produce shear stress levels described in the cerebral microvasculature (ζ = 1 dyn/cm 2 ) (20). After that time, Pf-iRBCs or uninfected RBCs were added to the flow system at the same concentration that is used for ratios of 40:1 iRBCs/HBMECs in static-conditions experiments (8 × 10 6 /ml) and allowed to circulate for 18 hours before fixation and processing for immunofluorescence.…”

Section: Flow Conditionsmentioning

confidence: 99%

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

Gállego-Delgado¹,

Basu-Roy²,

Ty³

et al. 2016

Journal of Clinical Investigation

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Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.

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“…The cluster formation assays under flow were carried out as described previously (Adams and Rowe, 2013; Lennartz et al, 2015) with minor modifications. Briefly, a µ-slide VI 0.4 (dimensions: 400 µm × 3.8 mm×17 mm) constructed of optical quality polymer.…”

Section: Methodsmentioning

confidence: 99%

Shed EBA-175 mediates red blood cell clustering that enhances malaria parasite growth and enables immune evasion

Paing

Salinas

Adams

et al. 2018

eLife

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Erythrocyte Binding Antigen of 175 kDa (EBA-175) has a well-defined role in binding to glycophorin A (GpA) during Plasmodium falciparum invasion of erythrocytes. However, EBA-175 is shed post invasion and a role for this shed protein has not been defined. We show that EBA-175 shed from parasites promotes clustering of RBCs, and EBA-175-dependent clusters occur in parasite culture. Region II of EBA-175 is sufficient for clustering RBCs in a GpA-dependent manner. These clusters are capable of forming under physiological flow conditions and across a range of concentrations. EBA-175-dependent RBC clustering provides daughter merozoites ready access to uninfected RBCs enhancing parasite growth. Clustering provides a general method to protect the invasion machinery from immune recognition and disruption as exemplified by protection from neutralizing antibodies that target AMA-1 and RH5. These findings provide a mechanistic framework for the role of shed proteins in RBC clustering, immune evasion, and malaria.

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The Effect of Anti-Rosetting Agents against Malaria Parasites under Physiological Flow Conditions

Cited by 12 publications

References 46 publications

Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes

Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

Shed EBA-175 mediates red blood cell clustering that enhances malaria parasite growth and enables immune evasion

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