Plasmodium-induced inflammation by uric acid.
Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.
Orengo
Jamie M
JM
Department of Medical Parasitology, New York University School of Medicine, New York, New York, USA.
Evans
James E
JE
Bettiol
Esther
E
Leliwa-Sytek
Aleksandra
A
Day
Karen
K
Rodriguez
Ana
A
D000818:Animals; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D019271:Hypoxanthine / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010961:Plasmodium / Q000276:immunology*; D010962:Plasmodium berghei / Q000502:physiology; D010963:Plasmodium falciparum / Q000502:physiology; D010967:Plasmodium yoelii / Q000502:physiology; D052939:Schizonts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*; D019820:Xanthine / Q000378:metabolism
D017077:Culture Media, Conditioned; D014409:Tumor Necrosis Factor-alpha; D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine