Characterization of VAR2CSA-deficient Plasmodium falciparum-infected erythrocytes selected for adhesion to the BeWo placental cell line

Yosaatmadja, Francisca; Andrews, Katherine Thea; Duffy, Michael; Brown, Graham V.; Beeson, James G.; Rogerson, Stephen J.

doi:10.1186/1475-2875-7-51

Cited by 16 publications

(17 citation statements)

References 41 publications

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“…2B and 4A). This EC 50 value is consistent with the activity range of CSA using FCR3-parasitized erythrocytes and BeWo cells [11], [27]. However, the obtained EC 50 value is significantly high when compared to published activity data using immobilized CSA (∼0.2 µg/ml) [28], or using other parasite strains (approximately 70% inhibition of CS2 binding with 10 µg/ml CSA) [27].…”

Section: Discussionsupporting

confidence: 86%

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An Image-Based Drug Susceptibility Assay Targeting the Placental Sequestration of Plasmodium falciparum-Infected Erythrocytes

Dossin

Hansen

et al. 2012

PLoS ONE

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Placental malaria is a significant cause of all malaria-related deaths globally for which no drugs have been developed to specifically disrupt its pathogenesis. To facilitate the discovery of antimalarial drugs targeting the cytoadherence process of Plasmodium-infected erythrocytes in the placenta microvasculature, we have developed an automated image-based assay for high-throughput screening for potent cytoadherence inhibitors in vitro. Parasitized erythrocytes were drug-treated for 24 h and then allowed to adhere on a monolayer of placental BeWo cells prior to red blood cell staining with glycophorin A antibodies. Upon image-acquisition, drug effects were quantified as the proportion of treated parasitized erythrocytes to BeWo cells compared to the binding of untreated iRBCs. We confirmed the reliability of this new assay by comparing the binding ratios of CSA- and CD36-panned parasites on the placental BeWo cells, and by quantifying the effects of chondroitin sulfate A, brefeldin A, and artemisinin on the binding. By simultaneously examining the drug effects on parasite viability, we could discriminate between cytoadherence-specific inhibitors and other schizonticidal compounds. Taken together, our data establish that the developed assay is highly suitable for drug studies targeting placental malaria, and will facilitate the discovery and rapid development of new therapies against malaria.

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Section: Discussionsupporting

confidence: 86%

“…Consistent with a predominant involvement of the CSA receptor in binding to the BeWo cells [8], [11], [27], soluble CSA efficiently inhibited the cytoadherence process with an EC 50 value of ∼12 µg/ml (Fig. 2B and 4A).…”

Section: Discussionsupporting

confidence: 75%

An Image-Based Drug Susceptibility Assay Targeting the Placental Sequestration of Plasmodium falciparum-Infected Erythrocytes

Dossin

Hansen

et al. 2012

PLoS ONE

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“…As described below, this may be an important feature in the pathogenesis of severe malaria, particularly cerebral malaria. In the placenta, chondroitin sulphate is a major receptor and a particular var gene encodes for the plasmodial protein which adheres to this placental receptor [13]. The sequestration in the placenta of pregnant women particularly in the primigravida is associated with low birth weight and other serious complications for the infant.…”

Section: Culture Of Gametocytesmentioning

confidence: 99%

The role of platelets in the pathogenesis of cerebral malaria

Cox

McConkey

2009

Cell. Mol. Life Sci.

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Malaria is a major cause of morbidity and mortality in the developing world and cerebral malaria is responsible for the majority of malaria-associated deaths. There is a strong association between thrombocytopenia and outcome in malaria, suggesting a role for platelets in the pathogenesis of malaria. This thrombocytopenia is likely due to platelet activation possibly through an interaction between PfEMP1 on plasmodium and CD36 on platelets. Platelet activation by plasmodium has two potential consequences. It can lead to the formation of micro-aggregates of infected red blood cells and platelets which can occlude blood vessels and it also leads to binding to and activation of the endothelium.

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“…This protein is the main target of the protective antibody response directed against the infected red cell surface Salanti et al, 2003). The parasite genome contains 60 var genes, each encoding a different red cell surface protein, but when var2sca is knocked out, parasites lose the ability to bind to CSA or to placenta (Duffy et al, 2006b;Viebig et al, 2005;Yosaatmadja et al, 2008). Parasites extracted from the placenta generally transcribe var2sca at high levels (Duffy et al, 2006a;Tuikue Ndam et al, 2005).…”

Section: Modelling Placental Malaria In Vitromentioning

confidence: 99%