{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:22:22Z","timestamp":1791156142809,"version":"4.1.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,9,15]]},"abstract":"<jats:p>\n                    Infection by\n                    <jats:named-content content-type=\"genus-species\">Plasmodium<\/jats:named-content>\n                    , the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a\n                    <jats:named-content content-type=\"genus-species\">Plasmodium<\/jats:named-content>\n                    -infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the\n                    <jats:italic>Hmox1<\/jats:italic>\n                    gene). When infected with\n                    <jats:italic>Plasmodium chabaudi chabaudi<\/jats:italic>\n                    (\n                    <jats:italic>Pcc<\/jats:italic>\n                    ), wild-type (\n                    <jats:italic>Hmox1<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    ) BALB\/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (\n                    <jats:italic>Hmox1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) BALB\/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in\n                    <jats:italic>Pcc<\/jats:italic>\n                    -infected DBA\/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in\n                    <jats:italic>Pcc<\/jats:italic>\n                    -infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after\n                    <jats:italic>Pcc<\/jats:italic>\n                    infection, NAC suppressed the development of hepatic failure in\n                    <jats:italic>Pcc<\/jats:italic>\n                    -infected DBA\/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against\n                    <jats:named-content content-type=\"genus-species\">Plasmodium<\/jats:named-content>\n                    infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0903419106","type":"journal-article","created":{"date-parts":[[2009,8,17]],"date-time":"2009-08-17T22:11:52Z","timestamp":1250547112000},"page":"15837-15842","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":252,"title":["Heme oxygenase-1 affords protection against noncerebral forms of severe malaria"],"prefix":"10.1073","volume":"106","author":[{"given":"Elsa","family":"Seixas","sequence":"first","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Gozzelino","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c2ngelo","family":"Chora","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Silva","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Larsen","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Rebelo","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Penido","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel P.","family":"Soares","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,9,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03342"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/415673a"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1148526"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2432"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-008-0368-5"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1586"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.20.9285"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.61.2.748"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505253322102"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2008.12.004"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410430603"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182008004344"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2008.07.003"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07201"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90222-C"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1184"},{"key":"e_1_3_3_17_2","first-page":"37","article-title":"N-acetylcysteine in severe falciparum malaria in Thailand","volume":"34","author":"Treeprasertsuk S","year":"2003","unstructured":"S Treeprasertsuk, et al., N-acetylcysteine in severe falciparum malaria in Thailand. 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J Immunol 162, 2837\u20132841 (1999).","journal-title":"J Immunol"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28844"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2217fje"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0903419106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T18:48:55Z","timestamp":1710528535000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0903419106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,15]]},"references-count":27,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2009,9,15]]}},"alternative-id":["10.1073\/pnas.0903419106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0903419106","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1728981.1246082","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,15]]},"assertion":[{"value":"2009-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-09-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}