{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:39:59Z","timestamp":1784605199714,"version":"3.55.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T00:00:00Z","timestamp":1474329600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T00:00:00Z","timestamp":1474329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cerebral malaria claims the life of millions of people each year, particularly those of children and is a major global public health problem. Thus, the identification of novel malaria biomarkers that could be utilized as diagnostic or therapeutic targets is becoming increasingly important. Using a proteomic approach, we previously identified unique biomarkers in the sera of malaria-infected individuals, including apolipoprotein E (ApoE). ApoE is the dominant apolipoprotein in the brain and has been implicated in several neurological disorders; therefore, we were interested in the potential role of ApoE in cerebral malaria. Here we report the first demonstration that cerebral malaria is markedly attenuated in ApoE<jats:sup>\u2212\/\u2212<\/jats:sup>mice. The protection provided by the absence of ApoE was associated with decreased sequestration of parasites and T cells within the brain and was determined to be independent from the involvement of ApoE receptors and from the altered lipid metabolism associated with the knock-out mice. Importantly, we demonstrated that treatment of mice with the ApoE antagonist heparin octasaccharide significantly decreased the incidence of cerebral malaria. Overall, our study indicates that the reduction of ApoE could be utilized in the development of therapeutic treatments aimed at mitigating the neuropathology of cerebral malaria.<\/jats:p>","DOI":"10.1038\/srep33615","type":"journal-article","created":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T10:38:11Z","timestamp":1474367891000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Absence of apolipoprotein E protects mice from cerebral malaria"],"prefix":"10.1038","volume":"6","author":[{"given":"Fikregabrail Aberra","family":"Kassa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Van Den Ham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Rainone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Fournier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Boilard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Olivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,20]]},"reference":[{"key":"BFsrep33615_CR1","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1038\/nature03342","volume":"434","author":"RW Snow","year":"2005","unstructured":"Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214\u2013217 (2005).","journal-title":"Nature"},{"key":"BFsrep33615_CR2","first-page":"385","volume":"119","author":"GG MacPherson","year":"1985","unstructured":"MacPherson, G. G., Warrell, M. J., White, N. J., Looareesuwan, S. & Warrell, D. A. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am. J. Pathol. 119, 385\u2013401 (1985).","journal-title":"Am. J. Pathol"},{"key":"BFsrep33615_CR3","doi-asserted-by":"publisher","first-page":"193","DOI":"10.4161\/viru.19013","volume":"3","author":"L Renia","year":"2012","unstructured":"Renia, L. et al. Cerebral malaria: mysteries at the blood-brain barrier. Virulence 3, 193\u2013201 (2012).","journal-title":"Virulence"},{"key":"BFsrep33615_CR4","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1586\/eri.10.90","volume":"8","author":"CC John","year":"2010","unstructured":"John, C. C., Kutamba, E., Mugarura, K. & Opoka, R. O. Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert Rev. Anti. Infect. Ther. 8, 997\u20131008 (2010).","journal-title":"Expert Rev. Anti. Infect. Ther"},{"key":"BFsrep33615_CR5","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1203\/PDR.0b013e3181eee738","volume":"68","author":"R Idro","year":"2010","unstructured":"Idro, R., Marsh, K., John, C. C. & Newton, C. R. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr. Res. 68, 267\u2013274 (2010).","journal-title":"Pediatr. Res."},{"key":"BFsrep33615_CR6","doi-asserted-by":"publisher","first-page":"e26495","DOI":"10.1371\/journal.pone.0026495","volume":"6","author":"FA Kassa","year":"2011","unstructured":"Kassa, F. A. et al. New Inflammation-Related Biomarkers during malaria infection. PLoS ONE 6, e26495 (2011).","journal-title":"PLoS ONE"},{"key":"BFsrep33615_CR7","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1146\/annurev.genom.1.1.507","volume":"1","author":"RW Mahley","year":"2000","unstructured":"Mahley, R. W. & Rall, S. C. Jr. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507\u2013537 (2000).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"BFsrep33615_CR8","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","volume":"261","author":"EH Corder","year":"1993","unstructured":"Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families. Science 261, 921\u2013923 (1993).","journal-title":"Science"},{"key":"BFsrep33615_CR9","first-page":"2083","volume":"148","author":"DR Premkumar","year":"1996","unstructured":"Premkumar, D. R., Cohen, D. L., Hedera, P., Friedland, R. P. & Kalaria, R. N. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer\u2019s disease. Am. J. Pathol. 148, 2083\u20132095 (1996).","journal-title":"Am. J. Pathol"},{"key":"BFsrep33615_CR10","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/S0197-0186(01)00050-X","volume":"39","author":"MJ LaDu","year":"2001","unstructured":"LaDu, M. J. et al. Apolipoprotein E and apolipoprotein E receptors modulate A\u03b2-induced glial neuroinflammatory responses. Neurochem. Int. 39, 427\u2013434 (2001).","journal-title":"Neurochem. Int."},{"key":"BFsrep33615_CR11","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","volume":"9","author":"CC Liu","year":"2013","unstructured":"Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106\u2013118 (2013).","journal-title":"Nat. Rev. Neurol."},{"key":"BFsrep33615_CR12","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1084\/jem.184.3.945","volume":"184","author":"P Sinnis","year":"1996","unstructured":"Sinnis, P., Willnow, T. E., Briones, M. R., Herz, J. & Nussenzweig, V. Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes. J. Exp. Med. 184, 945\u2013954 (1996).","journal-title":"J. Exp. Med."},{"key":"BFsrep33615_CR13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/1475-2875-7-211","volume":"7","author":"M Vignali","year":"2008","unstructured":"Vignali, M. et al. Interaction of an atypical Plasmodium falciparum ETRAMP with human apolipoproteins. Malar. J. 7, 211 (2008).","journal-title":"Malar. J."},{"key":"BFsrep33615_CR14","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1136\/jmg.40.5.348","volume":"40","author":"MA Wozniak","year":"2003","unstructured":"Wozniak, M. A. et al. Does apolipoprotein E polymorphism influence susceptibility to malaria? J. Med. Genet. 40, 348\u2013351 (2003).","journal-title":"J. Med. Genet."},{"key":"BFsrep33615_CR15","doi-asserted-by":"publisher","first-page":"4471","DOI":"10.1073\/pnas.89.10.4471","volume":"89","author":"JA Piedrahita","year":"1992","unstructured":"Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M. & Maeda, N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Nat. Acad. Sci. USA 89, 4471\u20134475 (1992).","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"BFsrep33615_CR16","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1128\/IAI.70.4.2049-2056.2002","volume":"70","author":"S Bagot","year":"2002","unstructured":"Bagot, S. et al. Susceptibility to Experimental Cerebral Malaria Induced by Plasmodium berghei ANKA in Inbred Mouse Strains Recently Derived from Wild Stock. Infect. Immun. 70, 2049\u20132056 (2002).","journal-title":"Infect. Immun"},{"key":"BFsrep33615_CR17","doi-asserted-by":"publisher","first-page":"4033","DOI":"10.1128\/IAI.00079-10","volume":"78","author":"FG Baptista","year":"2010","unstructured":"Baptista, F. G. et al. Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect. Immun. 78, 4033\u20134039 (2010).","journal-title":"Infect. Immun."},{"key":"BFsrep33615_CR18","doi-asserted-by":"publisher","first-page":"5364","DOI":"10.1128\/IAI.68.9.5364-5376.2000","volume":"68","author":"J Hearn","year":"2000","unstructured":"Hearn, J., Rayment, N., Landon, D. N., Katz, D. R. & de Souza, J. B. Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect. Immun. 68, 5364\u20135376 (2000).","journal-title":"Infect. Immun."},{"key":"BFsrep33615_CR19","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1111\/j.1462-5822.2011.01741.x","volume":"14","author":"HA del Portillo","year":"2012","unstructured":"del Portillo, H. A. et al. The role of the spleen in malaria. Cell. Microbiol. 14, 343\u2013355 (2012).","journal-title":"Cell. Microbiol"},{"key":"BFsrep33615_CR20","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.pt.2004.11.008","volume":"21","author":"CR Engwerda","year":"2005","unstructured":"Engwerda, C. R., Beattie, L. & Amante, F. H. The importance of the spleen in malaria. Trends in Parasitol. 21, 75\u201380 (2005).","journal-title":"Trends in Parasitol"},{"key":"BFsrep33615_CR21","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1017\/S0031182000080203","volume":"96","author":"CM Thumwood","year":"1988","unstructured":"Thumwood, C. M., Hunt, N. H., Clark, I. A. & Cowden, W. B. Breakdown of the blood-brain barrier in murine cerebral malaria. Parasitology 96, 579\u2013589 (1988).","journal-title":"Parasitology"},{"key":"BFsrep33615_CR22","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.4049\/jimmunol.170.4.2221","volume":"170","author":"J Nitcheu","year":"2003","unstructured":"Nitcheu, J. et al. Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. J. Immunol. 170, 2221\u20132228 (2003).","journal-title":"J. Immunol."},{"key":"BFsrep33615_CR23","doi-asserted-by":"publisher","first-page":"968","DOI":"10.4049\/jimmunol.1200688","volume":"189","author":"A Villegas-Mendez","year":"2012","unstructured":"Villegas-Mendez, A. et al. IFN-gamma-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. J. Immunol. 189, 968\u2013979 (2012).","journal-title":"J. Immunol."},{"key":"BFsrep33615_CR24","doi-asserted-by":"publisher","first-page":"6369","DOI":"10.4049\/jimmunol.169.11.6369","volume":"169","author":"E Belnoue","year":"2002","unstructured":"Belnoue, E. et al. On the Pathogenic Role of Brain-Sequestered \u03b1\u03b2 CD8+ T Cells in Experimental Cerebral Malaria. J. Immunol. 169, 6369\u20136375 (2002).","journal-title":"J. Immunol."},{"key":"BFsrep33615_CR25","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nrn2620","volume":"10","author":"G Bu","year":"2009","unstructured":"Bu, G. & Apolipoprotein, E. and its receptors in Alzheimer\u2019s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333\u2013344 (2009).","journal-title":"Nat. Rev. Neurosci."},{"key":"BFsrep33615_CR26","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1096\/fj.01-0463com","volume":"15","author":"MH Moghadasian","year":"2001","unstructured":"Moghadasian, M. H. et al. Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans. FASEB J. 15, 2623\u20132630 (2001).","journal-title":"FASEB J."},{"key":"BFsrep33615_CR27","doi-asserted-by":"publisher","first-page":"7134","DOI":"10.1073\/pnas.89.15.7134","volume":"89","author":"R Williamson","year":"1992","unstructured":"Williamson, R., Lee, D., Hagaman, J. & Maeda, N. Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-I. Proc. Nat. Acad. Sci. USA 89, 7134\u20137138 (1992).","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"BFsrep33615_CR28","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.ijpara.2006.02.005","volume":"36","author":"V Combes","year":"2006","unstructured":"Combes, V., Coltel, N., Faille, D., Wassmer, S. C. & Grau, G. E. Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier. Int. J. Parasitol. 36, 541\u2013546 (2006).","journal-title":"Int. J. Parasitol"},{"key":"BFsrep33615_CR29","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1182\/blood-2004-06-2206","volume":"105","author":"HC van der Heyde","year":"2005","unstructured":"van der Heyde, H. C., Gramaglia, I., Sun, G. & Woods, C. Platelet depletion by anti-CD41 (alphaIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines. Blood 105, 1956\u20131963 (2005).","journal-title":"Blood"},{"key":"BFsrep33615_CR30","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1074\/jbc.272.1.89","volume":"272","author":"DR Riddell","year":"1997","unstructured":"Riddell, D. R., Graham, A. & Owen, J. S. Apolipoprotein E inhibits platelet aggregation through the L-arginine: nitric oxide pathway. Implications for vascular disease. J. Biol. Chem. 272, 89\u201395 (1997).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33615_CR31","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/S0022-2275(20)38312-7","volume":"30","author":"K Desai","year":"1989","unstructured":"Desai, K., Bruckdorfer, K. R., Hutton, R. A. & Owen, J. S. Binding of apoE-rich high density lipoprotein particles by saturable sites on human blood platelets inhibits agonist-induced platelet aggregation. J. Lip. Res. 30, 831\u2013840 (1989).","journal-title":"J. Lip. Res."},{"key":"BFsrep33615_CR32","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.1096\/fj.09-135822","volume":"23","author":"D Faille","year":"2009","unstructured":"Faille, D. et al. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium. FASEB J. 23, 3449\u20133458 (2009).","journal-title":"FASEB J."},{"key":"BFsrep33615_CR33","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1182\/blood-2012-02-413047","volume":"120","author":"N Cloutier","year":"2012","unstructured":"Cloutier, N. et al. Platelets can enhance vascular permeability. Blood 120, 1334\u20131343 (2012).","journal-title":"Blood"},{"key":"BFsrep33615_CR34","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1053\/j.gastro.2006.11.002","volume":"132","author":"MD Gershon","year":"2007","unstructured":"Gershon, M. D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397\u2013414 (2007).","journal-title":"Gastroenterology"},{"key":"BFsrep33615_CR35","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1128\/CDLI.9.6.1145-1152.2002","volume":"9","author":"I Angulo","year":"2002","unstructured":"Angulo, I. & Fresno, M. Cytokines in the pathogenesis of and protection against malaria. Clin. Vaccine Immunol. 9, 1145\u20131152 (2002).","journal-title":"Clin. Vaccine Immunol."},{"key":"BFsrep33615_CR36","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1002\/eji.1830250307","volume":"25","author":"M Wysocka","year":"1995","unstructured":"Wysocka, M. et al. Interleukin-12 is required for interferon-gamma production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25, 672\u2013676 (1995).","journal-title":"Eur. J. Immunol."},{"key":"BFsrep33615_CR37","doi-asserted-by":"publisher","first-page":"14509","DOI":"10.1073\/pnas.0806727105","volume":"105","author":"RJ Lundie","year":"2008","unstructured":"Lundie, R. J. et al. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8\u03b1+ dendritic cells. Proc. Nat. Acad. Sci. USA. 105, 14509\u201314514 (2008).","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"BFsrep33615_CR38","doi-asserted-by":"publisher","first-page":"4814","DOI":"10.1073\/pnas.0801544105","volume":"105","author":"GS Campanella","year":"2008","unstructured":"Campanella, G. S. et al. Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc. Nat. Acad. Sci. USA 105, 4814\u20134819 (2008).","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"BFsrep33615_CR39","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.1021\/bi002417n","volume":"40","author":"J Dong","year":"2001","unstructured":"Dong, J. et al. Interaction of the N-terminal domain of apolipoprotein E4 with heparin. Biochemistry 40, 2826\u20132834 (2001).","journal-title":"Biochemistry"},{"key":"BFsrep33615_CR40","doi-asserted-by":"publisher","first-page":"41197","DOI":"10.1074\/jbc.M407962200","volume":"279","author":"V Hirsch-Reinshagen","year":"2004","unstructured":"Hirsch-Reinshagen, V. et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J. Biol. Chem. 279, 41197\u201341207 (2004).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33615_CR41","doi-asserted-by":"publisher","first-page":"40987","DOI":"10.1074\/jbc.M407963200","volume":"279","author":"SE Wahrle","year":"2004","unstructured":"Wahrle, S. E. et al. ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-secreted apoE. J. Biol. Chem. 279, 40987\u201340993 (2004).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33615_CR42","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/S0002-9440(10)62253-5","volume":"166","author":"V Combes","year":"2005","unstructured":"Combes, V. et al. ABCA1 gene deletion protects against cerebral malaria: potential pathogenic role of microparticles in neuropathology. Am. J. Pathol. 166, 295\u2013302 (2005).","journal-title":"Am. J. Pathol."},{"key":"BFsrep33615_CR43","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1046\/j.1365-2990.1999.00188.x","volume":"25","author":"H Brown","year":"1999","unstructured":"Brown, H. et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol. Appl. Neurobiol. 25, 331\u2013340 (1999).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"BFsrep33615_CR44","doi-asserted-by":"publisher","first-page":"207","DOI":"10.4269\/ajtmh.2001.64.207","volume":"64","author":"H Brown","year":"2001","unstructured":"Brown, H. et al. Blood-brain barrier function in cerebral malaria in Malawian children. Am. J. Trop. Med. Hyg. 64, 207\u2013213 (2001).","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"BFsrep33615_CR45","doi-asserted-by":"publisher","first-page":"7352","DOI":"10.1523\/JNEUROSCI.1002-05.2005","volume":"25","author":"MF Penet","year":"2005","unstructured":"Penet, M. F. et al. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J. Neurosci. 25, 7352\u20137358 (2005).","journal-title":"J. Neurosci."},{"key":"BFsrep33615_CR46","doi-asserted-by":"publisher","first-page":"3632","DOI":"10.4049\/jimmunol.1000944","volume":"185","author":"FH Amante","year":"2010","unstructured":"Amante, F. H. et al. Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. J. Immunol. 185, 3632\u20133642 (2010).","journal-title":"J. Immunol."},{"key":"BFsrep33615_CR47","doi-asserted-by":"publisher","first-page":"e18720","DOI":"10.1371\/journal.pone.0018720","volume":"6","author":"C Claser","year":"2011","unstructured":"Claser, C. et al. CD8+ T Cells and IFN-\u03b3 mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria. PLoS ONE 6, e18720 (2011).","journal-title":"PLoS ONE"},{"key":"BFsrep33615_CR48","doi-asserted-by":"publisher","first-page":"5645","DOI":"10.1128\/IAI.73.9.5645-5653.2005","volume":"73","author":"AJ Mitchell","year":"2005","unstructured":"Mitchell, A. J. et al. Early cytokine production is associated with protection from murine cerebral malaria. Infect. Immun. 73, 5645\u20135653(2005).","journal-title":"Infect. Immun."},{"key":"BFsrep33615_CR49","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.1128\/IAI.68.7.3909-3915.2000","volume":"68","author":"AJ Luty","year":"2000","unstructured":"Luty, A. J. et al. Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect. Immun. 68, 3909\u20133915 (2000).","journal-title":"Infect. Immun."},{"key":"BFsrep33615_CR50","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1046\/j.1365-3024.2002.00485.x","volume":"24","author":"L Malaguarnera","year":"2002","unstructured":"Malaguarnera, L., Pignatelli, S., Musumeci, M., Simpore, J. & Musumeci, S. Plasma levels of interleukin-18 and interleukin-12 in Plasmodium falciparum malaria. Parasite immunol. 24, 489\u2013492 (2002).","journal-title":"Parasite immunol"},{"key":"BFsrep33615_CR51","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1161\/01.RES.0000187467.67684.43","volume":"97","author":"K Ali","year":"2005","unstructured":"Ali, K., Middleton, M., Pure, E. & Rader, D. J. Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ. Res. 97, 922\u2013927 (2005).","journal-title":"Circ. Res."},{"key":"BFsrep33615_CR52","doi-asserted-by":"publisher","first-page":"4253","DOI":"10.1182\/blood-2002-05-1493","volume":"101","author":"E Belnoue","year":"2003","unstructured":"Belnoue, E. et al. CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101, 4253\u20134259 (2003).","journal-title":"Blood"},{"key":"BFsrep33615_CR53","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.amjsurg.2010.10.017","volume":"202","author":"KI Chuang","year":"2011","unstructured":"Chuang, K. I., Leung, B., Hsu, N. & Harris, H. W. Heparin protects against septic mortality via apoE-antagonism. Am. J. Surg. 202, 325\u2013335 (2011).","journal-title":"Am. J. Surg."},{"key":"BFsrep33615_CR54","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1016\/S0021-9258(17)35898-2","volume":"261","author":"KH Weisgraber","year":"1986","unstructured":"Weisgraber, K. H. et al. Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J. Biol. Chem. 261, 2068\u20132076 (1986).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33615_CR55","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/S0006-291X(86)80489-2","volume":"134","author":"AD Cardin","year":"1986","unstructured":"Cardin, A. D. et al. Binding of a high reactive heparin to human apolipoprotein E: identification of two heparin-binding domains. Biochem. Biophys. Res. Commun. 134, 783\u2013789 (1986).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep33615_CR56","doi-asserted-by":"crossref","first-page":"47","DOI":"10.14238\/pi20.1-2.1980.47-50","volume":"20","author":"M Munir","year":"1980","unstructured":"Munir, M., Tjandra, H., Rampengan, T. H., Mustadjab, I. & Wulur, F. H. Heparin in the treatment of cerebral malaria. Paediatr. Indones. 20, 47\u201350 (1980).","journal-title":"Paediatr. Indones"},{"key":"BFsrep33615_CR57","first-page":"59","volume":"31","author":"TH Rampengan","year":"1991","unstructured":"Rampengan, T. H. Cerebral malaria in children. Comparative study between heparin, dexamethasone and placebo. Paediatr. Indones. 31, 59\u201366 (1991).","journal-title":"Paediatr. Indones"},{"key":"BFsrep33615_CR58","unstructured":"World Health Organization. Management of severe malaria: a practial handbook, 3rd ed. (ed. WHO) 89 (WHO, 2012)."},{"key":"BFsrep33615_CR59","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1093\/jb\/mvm067","volume":"141","author":"R Sakiyama","year":"2007","unstructured":"Sakiyama, R. et al. Stimulation of hepatocyte growth factor production by heparin-derived oligosaccharides. J. Biochem. 141, 653\u2013660 (2007).","journal-title":"J. Biochem."},{"key":"BFsrep33615_CR60","doi-asserted-by":"publisher","first-page":"11468","DOI":"10.1073\/pnas.0503386102","volume":"102","author":"B Franke-Fayard","year":"2005","unstructured":"Franke-Fayard, B. et al. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc. Nat. Acad. Sci. USA 102, 11468\u201311473 (2005).","journal-title":"Proc. Nat. Acad. Sci. USA"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep33615","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33615.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33615.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T13:22:55Z","timestamp":1718803375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep33615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,20]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,14]]}},"alternative-id":["BFsrep33615"],"URL":"https:\/\/doi.org\/10.1038\/srep33615","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,20]]},"assertion":[{"value":"10 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"33615"}}