Open Access Research

Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria

Sarah J Higgins12, Katharine Xing1, Hani Kim1, Dylan C Kain1, Feng Wang1, Aggrey Dhabangi3, Charles Musoke3, Christine M Cserti-Gazdewich4, Kevin J Tracey5, Kevin C Kain16 and W Conrad Liles167*

  • * Corresponding author: W Conrad Liles wcliles@uw.edu

  • † Equal contributors

Author Affiliations

1 Sandra A Rotman Laboratory, McLaughlin-Rotman Centre for Global Health, University Health Network/University of Toronto, Toronto, ON, Canada

2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

3 Makerere University College of Health Sciences, Kampala, Uganda

4 Laboratory Medicine Program (Transfusion Medicine), University Health Network/University of Toronto, Toronto, ON, Canada

5 Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY, USA

6 Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, ON, Canada

7 Department of Medicine, University of Washington, 1959 Pacific Street, Box 354620, Seattle, WA, 98195-6420, USA

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Malaria Journal 2013, 12:105  doi:10.1186/1475-2875-12-105

Published: 19 March 2013

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.

Conclusion

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.

Keywords:
Severe malaria; HMGB1; Biomarker; Pathogenesis; Inflammation