Effects of Naturally-Acquired Malaria Pigment by Monocytes and Cyclooxygenase-2 Polymorpidsms on Prostaglandin-e2 production in cidldren with severe plasmodium falciparum Malaria
Anyona, Samuel Bonuke
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In malariaendemic regions of western Kenya, Plasmodium falciparum malaria manifestsclinically as severe malarial anemia [SMA; hemoglobin (Hb) <6.0gldL, with anydensity parasitemia]. The induction of prostaglandin (PG)-E2 production through cyclooxygenase(COX; prostaglandin-endoperoxide H synthase )-2 pathway is an important hostdefense mechanism against infectious agents. Although previous studies have shown thatPGE2 concentrations, COX-2 transcripts and protein levels are reduced in children withsevere malaria, the impact of in vivo malaria pigment-containing monocytes (PCM) onsystemic PGE2 production and COX-2 mRNA expression in children with SMA remainsunexplored. In addition, no studies to date have reported the association between COX-2genetic variation and susceptibility to SMA. As such, plasma and urinary PGE2 (measuredas the stable end metabolite: bicyclo-PGE) levels and COX-2 mRNA transcripts wereinvestigated in children (n=74; age<36 months) categorized into non-SMA (Hb~6.0gldL,with any density parasitemia; n=38) and SMA (n=36), presenting at Siaya District Hospital,western Kenya. In addition, the association between promoter variants COX-2 -512 C>T(rs20420), -608 T>C (rs204l9), -765 G>C (rs20417), -1132 G>A (rs204l5) and -1195A>G (rs689466), and susceptibility to SMA were investigated among parasitemic children(n=842) participating in the same study. The results revealed significantly decreasedplasma (P=0.001) and urinary (P<O.OOl) bicyclo-PGli, levels and COX-2 mRNAtranscripts (P=0.007) in children with SMA relative to non-SMA. Furthermore, decreasedplasma bicyclo-PGfi, levels were associated with insufficient erythropoiesis (reticulocyteproduction index; RPI<2.0, P=0.026), and an increasing number of pigmented monocytes(PCM) in plasma (P=0.03l) and urine (P=0.070). Additionally, COX-2 mRNA transcriptsdecreased with increasing levels of PCM (P=0.026). Analysis of co-infections in malariademonstrated significantly lower plasma bicyc\o- PGE2 levels in children with both malariaand HIV-l or bacterial [Pf (+) HIV-l (+) Bac. (+)], relative to children with falciparummalaria mono-infection [Pf (+)] (P<O.OOl).In addition, COX-2 mRNA transcripts weredecreased in children with [Pf (+) HIV-l (+) Bac. (+)] (P=0.023). Analyses of COX-2 promoter polymorphic genotypes and their haplotype constructs using binary logisticregression modeling, controlling for confounding effects of age, gender, sickle cell trait,HIV-linfectionand exposure, G6PD deficiency, a+ thalassemia and bacterial infections,led no effect of individual genotypes on SMA. However carriers of the -5l2CI -608CIr_e7v6e5aCI _1195A (CCCA) haplotype were protected against SMA (P=0.043) and presentedwith increased plasma bicyclo-PGE2levels (P=0.011). By contrast, carriers ofthe TTGGhaplotype were at an increased risk of developing SMA (P=0.077). Similarly, carriers ofthe_608C/-765C (CC) haplotype had a 73% reduced risk of developing SMA (P=0.037)and increased plasma (P=0.011) and urinary (P=0.045) bicyclo-Pfils, levels. However,carriers of the TG haplotype were at an increased risk of developing SMA (P=0.062) andpresented with lower urinary bicyclo-PGE2levels (P=0.001) and COX-2 mRNA transcripts(P=0.025). Taken together, these results illustrate that COX-2 mRNA expression is downregulatedin children with SMA, and associated co-infections, resulting in decreased invivo PGE2production, driven at least in part, by naturally acquired Plasmodium pigment(hemozoin) by monocytes. COX-2 derived PGE2 is also regulated by promoter variantsthat may impact on erythropoiesis, and thereby, influence the development of SMA.