A Potential Role for Plasma Uric Acid in the Endothelial Pathology of Plasmodium falciparum malaria

Neida K Mita-Mendoza,Drissa Konate,Mory Doumbouya,Saibou Doumbia,Rick M Fairhurst,Tatiana M Lopera-Mesa,Michael P Fay,Mahamadou Diakite,Diana L Van De Hoef,Ana Rodriguez,Carole A Long,Leopoldo Santos-Argumedo,Wenjuan Gu,Jennifer M Anderson,James G Beeson

doi:10.1371/journal.pone.0054481

Abstract

BackgroundInflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, ‘parasite-derived’ uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.Methodology/Principal FindingsWe measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5–17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.Conclusions/SignificanceElevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084).

Highlights

Plasmodium falciparum (Pf) malaria, a major cause of childhood morbidity and mortality in sub-Saharan Africa, is characterized by significant impairment of the microvascular endothelium [1]
Since elevated uric acid (UA) levels are associated with endothelial inflammation in a variety of non-malaria diseases, and some of the aforementioned cytokines are produced by microvascular endothelial cells (MVECs), we explored whether elevated UA levels may contribute to the endothelial pathology of P. falciparum malaria
We hypothesized that UA contributes to the pathogenesis of P. falciparum malaria by causing endothelial pathology, as it does in non-malaria diseases

Summary

Introduction

Plasmodium falciparum (Pf) malaria, a major cause of childhood morbidity and mortality in sub-Saharan Africa, is characterized by significant impairment of the microvascular endothelium [1]. It has been proposed that the synchronous rupture of schizonts in microvessels may achieve high local UA levels by releasing UA from the RBC cytoplasm, resulting in the formation of UA precipitates that are inflammatory for mononuclear cells. In another – not mutually exclusive – model, UA precipitates form in the cytosol of intraerythrocytic parasites, are released at schizont rupture, and directly activate mononuclear and dendritic cells [17] (van de Hoef et al, submitted). ‘parasite-derived’ uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria

Methods

Results

Conclusion