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

Nguyen, Suong T.; Du, Daniel; Wychrij, Daniel; Cain, Matthew D.; Wu, Qingping; Klein, Robyn S.; Russo, Ilaria; Goldberg, Daniel E.

Authors

Suong T. Nguyen

Daniel Du

Daniel Wychrij

Matthew D. Cain

Qingping Wu

Robyn S. Klein

Daniel E. Goldberg



Contributors

Abstract

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

Citation

Nguyen, S. T., Du, D., Wychrij, D., Cain, M. D., Wu, Q., Klein, R. S., …Goldberg, D. E. (2023). Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria. Proceedings of the National Academy of Sciences of the United States of America, 120(26), Article e2306318120. https://doi.org/10.1073/pnas.2306318120

Journal Article Type Article
Acceptance Date May 19, 2023
Online Publication Date Jun 12, 2023
Publication Date Jun 27, 2023
Deposit Date Jun 27, 2023
Journal Proceedings of the National Academy of Sciences
Print ISSN 0027-8424
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 120
Issue 26
Article Number e2306318120
DOI https://doi.org/10.1073/pnas.2306318120
Keywords Multidisciplinary
Additional Information Received: 2023-04-18; Accepted: 2023-05-19; Published: 2023-06-12