Interplay of Plasmodium falciparum and thrombin in brain endothelial barrier disruption

Marion Avril,Mary-Margaret Dols,Joseph D Smith,Max Benjamin

doi:10.1038/s41598-019-49530-1

Marion Avril, Mary-Margaret Dols + Show 2 more

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https://doi.org/10.1038/s41598-019-49530-1

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Journal: Scientific Reports	Publication Date: Sep 11, 2019
Citations: 22	License type: open-access

Affiliation: Seattle University, University of Washington

Abstract

Recent concepts suggest that both Plasmodium falciparum factors and coagulation contribute to endothelial activation and dysfunction in pediatric cerebral malaria (CM) pathology. However, there is still limited understanding of how these complex inflammatory stimuli are integrated by brain endothelial cells. In this study, we examined how mature-stage P. falciparum infected erythrocytes (IE) interact with tumor necrosis factor α (TNFα) and thrombin in the activation and permeability of primary human brain microvascular endothelial cell (HBMEC) monolayers. Whereas trophozoite-stage P. falciparum-IE have limited effect on the viability of HBMEC or the secretion of pro-inflammatory cytokines or chemokines, except at super physiological parasite-host cell ratios, schizont-stage P. falciparum-IE induced low levels of cell death. Additionally, schizont-stage parasites were more barrier disruptive than trophozoite-stage P. falciparum-IE and prolonged thrombin-induced barrier disruption in both resting and TNFα-activated HBMEC monolayers. These results provide evidence that parasite products and thrombin may interact to increase brain endothelial permeability.

Highlights

Cerebral malaria (CM) is a life-threatening complication associated with the sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microcirculation[1,2,3,4]
We investigated the interaction of mature P. falciparum-IE and thrombin in co-culture models with primary human brain microvascular endothelial cells (HBMEC)
Primary HBMEC responded to 10 nM thrombin treatment with the characteristic rapid decrease in cell index (CI) that reached a maximum by 15–20 min and returned to baseline by 1 hr

Summary

Introduction

Cerebral malaria (CM) is a life-threatening complication associated with the sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microcirculation[1,2,3,4]. The vascular dysfunction in cerebral malaria is believed to result from a combination of microvascular obstruction and tissue perfusion abnormalities[8,9], altered coagulation[10,11], systemic and local inflammatory processes[12], and damaging parasite products (reviewed in Miller et al.[13]). EPCR-binding var transcripts are linked to severe brain swelling in CM35 and recombinant parasite domains compete with APC for binding to EPCR26,36–39. These findings strongly implicate both parasite factors and pro-coagulant processes in cerebral malaria pathology, the molecular mechanisms of how these complex inflammatory stimuli translate into endothelial activation and blood-brain barrier dysfunction remain only partially understood. Our study suggests that mature-stage parasites differ in their barrier-disruptive activity and that schizont-stage P. falciparum-IE delay endothelial cell recovery from thrombin-induced barrier disruption

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