{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:15Z","timestamp":1787005755004,"version":"build-2736575974"},"reference-count":68,"publisher":"National Academy of Sciences","issue":"26","license":[{"start":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T00:00:00Z","timestamp":1686528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI126909"],"award-info":[{"award-number":["AI126909"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI106688"],"award-info":[{"award-number":["AI106688"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,27]]},"abstract":"<jats:p>\n                    Histidine-rich protein II (HRPII) is secreted by\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    \u00a0during 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\u2013brain 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\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    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-1\u03b2 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306318120","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T15:21:04Z","timestamp":1686583264000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4704-2270","authenticated-orcid":false,"given":"Suong T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Du","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Wychrij","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Cain","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingping","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn S.","family":"Klein","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Russo","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3529-8399","authenticated-orcid":false,"given":"Daniel E.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.30875\/6c551ba0-en"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu293"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(05)70247-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.103.4.1269"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.29.8.1629-1634.1991"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","unstructured":"J. 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