Volume 88, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Severe malaria is characterized by a massive release of proinflammatory cytokines in the context of sequestration of parasitized and normal red cells (RBCs). High-mobility group box 1 (HMGB1) is a DNA- and heparin-binding protein that also acts as a cytokine when released from cells in the extracellular milieu after a proinflammatory stimulus. In this study, we have measured the circulating levels of HMGB1 in 76 children with severe or uncomplicated malaria. Sera from both severe ( = 0.0022) and uncomplicated ( = 0.0049) patients had significantly higher circulating HMGB1 levels compared with healthy controls. Elevated HMGB1 in patients with ongoing infections might prolong inflammation and the febrile state of malaria and could offer a potential target for therapeutic intervention.


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  1. World Health Organization, 2008. World Malaria Report 2008. Geneva: World Health Organization. [Google Scholar]
  2. Maitland K, Marsh K, , 2004. Pathophysiology of severe malaria in children. Acta Trop 90: 131140.[Crossref] [Google Scholar]
  3. Carlson J, Helmby H, Hill AV, Brewster D, Greenwood BM, Wahlgren M, , 1990. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet 336: 14571460.[Crossref] [Google Scholar]
  4. Newton CR, Warn PA, Winstanley PA, Peshu N, Snow RW, Pasvol G, Marsh K, , 1997. Severe anaemia in children living in a malaria endemic area of Kenya. Trop Med Int Health 2: 165178.[Crossref] [Google Scholar]
  5. Clark IA, Virelizier JL, Carswell EA, Wood PR, , 1981. Possible importance of macrophage-derived mediators in acute malaria. Infect Immun 32: 10581066. [Google Scholar]
  6. Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM, , 1990. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 336: 12011204.[Crossref] [Google Scholar]
  7. Ueda T, Yoshida M, , 2010. HMGB proteins and transcriptional regulation. Biochim Biophys Acta 1799: 114118.[Crossref] [Google Scholar]
  8. Harris HE, Andersson U, Pisetsky DS, , 2012. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nature Reviews Rheumatology 8: 195202.[Crossref] [Google Scholar]
  9. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Erlandsson-Harris H, Andersson U, Yang H, Tracey KJ, Andersson J, Palmblad JE, , 2003. High mobility group 1 B-box mediates activation of human endothelium. J Intern Med 254: 375385.[Crossref] [Google Scholar]
  10. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ, , 1999. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248251.[Crossref] [Google Scholar]
  11. Ito Y, Torii Y, Ohta R, Imai M, Hara S, Kawano Y, Matsubayashi T, Inui A, Yoshikawa T, Nishimura N, Ozaki T, Morishima T, Kimura H, , 2011. Increased levels of cytokines and high-mobility group box 1 are associated with the development of severe pneumonia, but not acute encephalopathy, in 2009 H1N1 influenza-infected children. Cytokine 56: 180187.[Crossref] [Google Scholar]
  12. Gaini S, Pedersen SS, Koldkjaer OG, Pedersen C, Moller HJ, , 2007. High mobility group box-1 protein in patients with suspected community-acquired infections and sepsis: a prospective study. Crit Care 11: R32.[Crossref] [Google Scholar]
  13. Alleva LM, Yang H, Tracey KJ, Clark IA, , 2005. High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria. Trans R Soc Trop Med Hyg 99: 171174.[Crossref] [Google Scholar]
  14. John CC, Opika-Opoka R, Byarugaba J, Idro R, Boivin MJ, , 2006. Low levels of RANTES are associated with mortality in children with cerebral malaria. J Infect Dis 194: 837845.[Crossref] [Google Scholar]
  15. Karlsson S, Pettila V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E, , 2008. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med 34: 10461053.[Crossref] [Google Scholar]
  16. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, Lee ML, Andersson J, Tokics L, Treutiger CJ, , 2005. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 33: 564573.[Crossref] [Google Scholar]
  17. Angus DC, Yang L, Kong L, Kellum JA, Delude RL, Tracey KJ, Weissfeld L, , 2007. Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 35: 10611067.[Crossref] [Google Scholar]
  18. Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, Bollaert PE, , 2007. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med 33: 13471353.[Crossref] [Google Scholar]
  19. Alleva LM, Budd AC, Clark IA, , 2008. Systemic release of high mobility group box 1 protein during severe murine influenza. J Immunol 181: 14541459.[Crossref] [Google Scholar]
  20. Ling Y, Yang ZY, Yin T, Li L, Yuan WW, Wu HS, Wang CY, , 2011. Heparin changes the conformation of high-mobility group protein 1 and decreases its affinity toward receptor for advanced glycation endproducts in vitro . Int Immunopharmacol 11: 187193.[Crossref] [Google Scholar]
  21. Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR, Kennedy TP, , 2010. Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol 299: C97C110.[Crossref] [Google Scholar]
  22. Mercereau-Puijalon O, Guillotte M, Vigan-Womas I, , 2008. Rosetting in Plasmodium falciparum: a cytoadherence phenotype with multiple actors. Transfus Clin Biol 15: 6271.[Crossref] [Google Scholar]
  23. Vogt AM, Barragan A, Chen Q, Kironde F, Spillmann D, Wahlgren M, , 2003. Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1. Blood 101: 24052411.[Crossref] [Google Scholar]
  24. Vogt AM, Pettersson F, Moll K, Jonsson C, Normark J, Ribacke U, Egwang TG, Ekre HP, Spillmann D, Chen Q, Wahlgren M, , 2006. Release of sequestered malaria parasites upon injection of a glycosaminoglycan. PLoS Pathog 2: e100.[Crossref] [Google Scholar]
  25. Leitgeb AM, Blomqvist K, Cho-Ngwa F, Samje M, Nde P, Titanji V, Wahlgren M, , 2011. Low anticoagulant heparin disrupts Plasmodium falciparum rosettes in fresh clinical isolates. Am J Trop Med Hyg 84: 390396.[Crossref] [Google Scholar]

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  • Received : 29 Aug 2012
  • Accepted : 30 Nov 2012
  • Published online : 03 Apr 2013

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