Reduced Systemic Bicyclo-Prostaglandin-E2 and Cyclooxygenase-2 Gene Expression are Associated with Inefficient Erythropoiesis and Enhanced Uptake of Monocytic Hemozoin in Children with Severe Malarial Anemia

Abstract

In holoendemic Plasmodium falciparum transmission areas, severe malaria primarily occurs in children <48 mos. and manifests as severe malarial anemia [SMA; hemoglobin (Hb)<6.0 g/dL]. Induction of high levels of prostaglandin-E2 (PGE2) through inducible cyclooxygenase-2 (COX-2) is an important host defense mechanism against invading pathogens. We have previously shown that COX-2-derived PGE2 levels are reduced in children residing in hyperendemic transmission regions with cerebral malaria and in those with mixed sequelae of anemia and hyperparasitemia. Our in vitro studies further demonstrated that reduced PGE2 was due to down-regulation of COX-2 gene products following phagocytosis of malarial pigment (hemozoin, PfHz). However, since COX-2-PGE2 pathways and the impact of naturally acquired PfHz on erythropoietic responses have not been determined in children with SMA, plasma and urinary bicyclo-PGE2/creatinine and leukocytic COX-2 transcripts were determined in parasitized children (<36 mos.) stratified into SMA (n=36) and non-SMA (Hb≥6.0 g/dL; n=38). Children with SMA had significantly reduced plasma (P=0.001) and urinary (P<0.001) bicyclo-PGE2/creatinine, and COX-2 transcripts (P=0.007). There was a significant positive association between Hb and both plasma (r=0.363, P=0.002) and urinary (r=0.500, P=0.001)] bicyclo-PGE2/creatinine. Furthermore, decreased systemic bicyclo-PGE2/creatinine was associated with inefficient erythropoiesis (i.e., reticulocyte production index; RPI<2.0, P=0.026). Additional analyses demonstrated that plasma (P=0.031) and urinary (P=0.070) bicyclo-PGE2/creatinine and COX-2 transcripts (P=0.026) progressively declined with increasing concentrations of naturally acquired PfHz by monocytes. Results presented here support a model in which reduced COX-2-derived PGE2, driven in part by naturally acquired PfHz by monocytes, promotes decreased erythropoietic responses in children with SMA.