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

Sarah J Higgins,Feng Wang,Hani Kim,Aggrey Dhabangi,Christine M Cserti-Gazdewich,Katharine Xing,W Conrad Liles,Charles Musoke,Kevin J Tracey,Dylan C Kain,Kevin C Kain

doi:10.1186/1475-2875-12-105

Abstract

BackgroundSevere 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.MethodsPlasma 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.ResultsElevated 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.ConclusionThese 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.

Highlights

Severe falciparum malaria (SM) pathogenesis has been attributed, in part, to deleterious systemic host inflammatory responses to infection
Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria In this study, extracellular High mobility group box 1 (HMGB1) was quantified in plasma from 103 febrile Ugandan children with either uncomplicated malaria (UM) or severe malaria (SM) (Table 1) by enzyme-linked immunosorbent assay (ELISA) [9]
Admission levels of HMGB1 were significantly higher in children with smear-confirmed severe P. falciparum malaria compared to UM (Figure 1A)

Summary

Introduction

Severe falciparum malaria (SM) pathogenesis has been attributed, in part, to deleterious systemic host inflammatory responses to infection. Preclinical studies have reported that neutralizing anti-HMGB1 antibodies prevents organ damage and lethality in established models of experimental sepsis (both endotoxin induced- and cecal ligation and puncture (CLP)-induced models) [6,7,8], even with late administration [7]. These studies suggest that HMGB1 may represent a novel therapeutic target to reduce deleterious inflammation during systemic infection [5]

Methods

Results

Conclusion