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Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria.
Title | Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Higgins, SJ, Xing, K, Kim, H, Kain, DC, Wang, F, Dhabangi, A, Musoke, C, Cserti-Gazdewich, CM, Tracey, KJ, Kain, KC, W Liles, C |
Journal | Malar J |
Volume | 12 |
Pagination | 105 |
Date Published | 2013 |
ISSN | 1475-2875 |
Keywords | Animals, Antibodies, Neutralizing, Biological Markers, Case-Control Studies, Child, Child, Preschool, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, HMGB1 Protein, Humans, Immunoglobulins, Intravenous, Infant, Malaria, Malaria, Falciparum, Male, Mice, Mice, Inbred C57BL, Prognosis, Prospective Studies, ROC Curve, Treatment Outcome, Uganda |
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. |
DOI | 10.1186/1475-2875-12-105 |
Alternate Journal | Malar. J. |
PubMed ID | 23506269 |