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Van De Hoef D.L.; Orengo J.; Coppens I.; Rodriguez A.
"Plasmodium falciparum-infected erythrocytes contain uric acid precipitates that are highly inflammatory" [Meeting Abstract]
American journal of tropical medicine & hygiene 2010 ; 83(5 SUPPL 1):130-130
Malaria life-threatening pathology is caused or exacerbated by excessive inflammatory responses in the host. Further understanding of the mechanisms involved in this process is needed to develop more effective therapies against malaria-induced pathology. We previously defined uric acid (UA) as a mediator of malaria-induced inflammation in mouse and human cells as reported previously. We have now discovered that Plasmodium falciparum-infected erythrocytes contain UA precipitates. Using both immunofluorescence with specific antibodies and lysate fractionation, we have detected UA precipitates in P. falciparum-infected erythrocytes in all cycle stages. UA precipitates are localized in the Plasmodium cytosol and are released into the medium upon schizont rupture. The inflammatory properties of UA precipitates (also named crystals) are well known because they are the causative agent of gout and are also considered a danger signal for the immune system. Direct release of UA precipitates in the blood upon schizont rupture may cause strong inflammatory responses during malaria infection. We found that addition of UA inhibitory drugs, allopurinol and uricase, reduced secretion of inflammatory cytokines (TNF, IL-1 p and IL-6) from human peripheral blood mononuclear cells in response to Plasmodium-infected erythrocytes, suggesting that a decrease in UA levels in vivo may reduce the host inflammatory response and pathology. We obtained intracellular UA precipitates derived from Plasmodium-infected erythrocytes. These precipitates caused increased expression of the dendritic cell activation markers, CD40, CD80 and CD86 in vitro. This inflammatory effect was sensitive to uricase treatment, confirming their identity. This suggests that Plasmodium-derived UA activates the host inflammatory response and may contribute towards malaria pathology. Inhibiting UA formation may therefore decrease malaria-induced pathology, and this will establish the basis for developing specific therapies against this devastating disease

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