A potential role for plasma uric acid in the endothelial pathology of Plasmodium falciparum malaria.
BACKGROUND
Inflammatory 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.


RESULTS
We 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
Elevated 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).
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
Neida K
NK
Mita-Mendoza
Diana L
DL
van de Hoef
Tatiana M
TM
Lopera-Mesa
Saibou
S
Doumbia
Drissa
D
Konate
Mory
M
Doumbouya
Wenjuan
W
Gu
Jennifer M
JM
Anderson
Leopoldo
L
Santos-Argumedo
Ana
A
Rodriguez
Michael P
MP
Fay
Mahamadou
M
Diakite
Carole A
CA
Long
Rick M
RM
Fairhurst
D019040:E-Selectin / Q000097:blood; D004727:Endothelium / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D004912:Erythrocytes / Q000469:parasitology / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000469:parasitology / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016778:Malaria, Falciparum / Q000097:blood* / Q000469:parasitology / Q000473:pathology; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D010963:Plasmodium falciparum / Q000378:metabolism / Q000472:pathogenicity; D010974:Platelet Aggregation / Q000502:physiology; D018180:Thrombomodulin / Q000097:blood; D014527:Uric Acid / Q000097:blood*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D019040:E-Selectin; C546931:THBD protein, human; D018180:Thrombomodulin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid; D005337:Fibrin