title: Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria.
abstract: BACKGROUND
  Severe falciparum malaria (SM) pathogenesis has been attributed, in part, to deleterious systemic host inflammatory responses to infection. High mobility group box 1 (HMGB1) protein is an important mediator of inflammation implicated in sepsis pathophysiology.
  
  
  METHODS
  Plasma levels of HMGB1 were quantified in a cohort of febrile Ugandan children with Plasmodium falciparum infection, enrolled in a prospective observational case-controlled study, using a commercial enzyme-linked immunosorbent assay. The utility of HMGB1 to distinguish severe malaria (SM; n = 70) from uncomplicated malaria (UM; n = 33) patients and fatal (n = 21) versus non-fatal (n = 82) malaria, at presentation, was examined. Receiver operating characteristic curve analysis was used to assess the prognostic accuracy of HMGB1. The ability of P. falciparum-parasitized erythrocytes to induce HMGB1 from peripheral blood mononuclear cells was assessed in vitro. The effect of an anti-HMGB1 neutralizing antibody on disease outcome was assessed in the experimental Plasmodium berghei ANKA rodent parasite model of SM. Mortality and parasitaemia was assessed daily and compared to isotype antibody-treated controls.
  
  
  RESULTS
  Elevated plasma HMGB1 levels at presentation were significantly associated with SM and a subsequent fatal outcome in paediatric patients with P. falciparum infection. In vitro, parasitized erythrocytes induced HMGB1 release from human peripheral blood mononuclear cells. Antibody-mediated neutralization of HMGB1 in the experimental murine model of severe malaria failed to reduce mortality.
  
  
  CONCLUSIONS
  These data suggest that elevated HMGB1 is an informative prognostic marker of disease severity in human SM, but do not support HMGB1 as a viable target for therapeutic intervention in experimental murine SM.
authors.affiliation: Sandra A Rotman Laboratory, McLaughlin-Rotman Centre for Global Health, University Health Network/University of Toronto, Toronto, ON, Canada.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Higgins
authors.forename: Katharine
authors.initials: K
authors.lastname: Xing
authors.forename: Hani
authors.initials: H
authors.lastname: Kim
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Kain
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Aggrey
authors.initials: A
authors.lastname: Dhabangi
authors.forename: Charles
authors.initials: C
authors.lastname: Musoke
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cserti-Gazdewich
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007223:Infant; D008288:Malaria / Q000188:drug therapy / Q000473:pathology; D016778:Malaria, Falciparum / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D024243:HMGB1 Protein; D016756:Immunoglobulins, Intravenous