Interplay of Plasmodium falciparum and thrombin in brain endothelial barrier disruption

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Cerebral malaria (CM) involves endothelial activation and dysfunction.
• Plasmodium falciparum (P. falciparum) and coagulation factors are implicated in CM.
• Limited understanding exists on how brain endothelial cells integrate these inflammatory stimuli.

Purpose of the Study:

• To investigate the interaction between P. falciparum infected erythrocytes (IE) and inflammatory mediators (TNFα, thrombin) in brain endothelial cells.
• To determine the effect of mature-stage P. falciparum-IE on human brain microvascular endothelial cell (HBMEC) activation and permeability.

Main Methods:

• Primary human brain microvascular endothelial cell (HBMEC) monolayers were used.
• Exposure to trophozoite-stage and schizont-stage P. falciparum-IE.
• Co-exposure with tumor necrosis factor α (TNFα) and thrombin.
• Assessment of HBMEC viability, cytokine/chemokine secretion, and barrier permeability.

Main Results:

• Schizont-stage P. falciparum-IE induced low levels of HBMEC cell death.
• Schizont-stage IE were more barrier disruptive than trophozoite-stage IE.
• Schizont-stage IE prolonged thrombin-induced barrier disruption in both resting and TNFα-activated HBMEC.

Conclusions:

• Parasite products from mature-stage P. falciparum IE interact with thrombin.
• This interaction significantly increases brain endothelial permeability.
• Findings suggest a combined mechanism contributing to pediatric cerebral malaria pathology.