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
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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
