Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction

Area of Science:

• Immunology
• Cell Biology
• Parasitology

Background:

• Severe Plasmodium falciparum malaria is linked to endothelial cell activation and increased vascular permeability.
• The precise mechanisms by which endothelial cells are activated by parasite components remain unclear.

Purpose of the Study:

• To investigate the role of Plasmodium falciparum histones in endothelial cell activation and vascular permeability.
• To elucidate the signaling pathways involved in histone-mediated endothelial responses.

Main Methods:

• Primary human dermal microvascular endothelial cells were stimulated with Plasmodium falciparum histones (HeH) and recombinant PfH3.
• Signaling pathways (Src kinases, p38 MAPK) were analyzed.
• Endothelial permeability and cell death were assessed.
• Nucleosomes in parasite cultures and patient plasma were detected.
• Functional effects of activated protein C were evaluated.

Main Results:

• Plasmodium falciparum histones (HeH and PfH3) directly induced IL-8 production and inflammatory mediator release from endothelial cells via Src kinases and p38 MAPK.
• Histone-specific antibodies blocked these stimulatory effects.
• Parasite histone release from infected erythrocytes was observed.
• Histones increased endothelial permeability, disrupted junctional proteins, and caused cell death.
• Human and parasite nucleosomes were detected in malaria patient plasma, correlating with disease severity.

Conclusions:

• Host and parasite-derived histones play a pathogenic role in severe Plasmodium falciparum malaria.
• Histones contribute to endothelial activation, inflammation, and vascular dysfunction.
• Targeting histones may offer therapeutic strategies for severe malaria.