Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria

• DOI: 10.1073/pnas.2306318120
• Publication Date: 2023-06-12T19:21:04Z
• Authors: Suong T. Nguyen; Daniel Du; Daniel Wychrij; Matthew D. Cain; Qingping Wu; Robyn S. Klein; Ilaria Russo; Daniel E. Goldberg
• Keywords: Cerebral Malaria; Vascular permeability

Histidine-rich protein II (HRPII) is secreted by Plasmodium falciparum during the blood stage of malaria infection. High plasma levels HRPII are associated with cerebral malaria, a severe and highly fatal complication malaria. has been shown to induce vascular leakage, hallmark in blood–brain barrier (BBB) animal models. We have discovered an important mechanism for BBB disruption that driven unique features HRPII. By characterizing serum from infected patients produced P. parasites culture, we found exists large multimeric particles 14 polypeptides richly laden up 700 hemes per particle. Heme loading required efficient binding internalization via caveolin-mediated endocytosis hCMEC/D3 microvascular endothelial cells. Upon acidification endolysosomes, two-thirds released acid-labile sites metabolized heme oxygenase 1, generating ferric iron reactive oxygen species. Subsequent activation NLRP3 inflammasome IL-1β secretion resulted leakage. Inhibition these pathways sequestration, chelation, or anti-inflammatory drugs protected integrity culture model HRPII:heme. Increased permeability was seen after injection young mice heme-loaded (HRPII:heme) but not heme-depleted propose infection, HRPII:heme nanoparticles bloodstream deliver overwhelming load cells cause inflammation edema. Disrupting this process opportunity targeted adjunctive therapies reduce morbidity mortality