Abstract
ABSTRACTIntercellular 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.
Highlights
Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria
To enrich for purer domain cassette 13 (DC13) var-expressing parasite lines, IT4var07 was isolated by limited-dilution cloning and IT4var07 and HB3var03 parasite lines were selected by repeated panning on a transformed human brain microvascular endothelial cell (THBMEC) line
Analysis of PfEMP1 protein binding has revealed that ICAM-1 binding domains can be linked to either group B and C (CD36-binding) or group A (EPCR-binding) head structures [17]
Summary
Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria It remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. 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. We isolated highly monoclonal parasite lines expressing group A DC13 PfEMP1 variants previously shown to have high human brain and other endothelial cell type binding activity [7, 23] and characterized their EPCR- and ICAM-1binding activities. We investigated how functional diversification of ICAM-1-binding parasite lines with CD36- or EPCR-binding head structures influences parasite binding to resting or tumor necrosis factor alpha (TNF-␣)-activated microvascular endothelial cells from the lung or brain
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