Abstract
The role of infection in erythropoietic dysfunction is poorly understood. In children with P. falciparum malaria, the by-product of hemoglobin digestion in infected red cells (hemozoin) is associated with the severity of anemia which is independent of circulating levels of the inflammatory cytokine tumor necrosis alpha (TNF-α). To gain insight into the common and specific effects of TNF-α and hemozoin on erythropoiesis, we studied the gene expression profile of purified primary erythroid cultures exposed to either TNF-α (10ng/ml) or to hemozoin (12.5μg/ml heme units) for 24 hours. Perturbed gene function was assessed using co-annotation of associated gene ontologies and expression of selected genes representative of the profile observed was confirmed by real time PCR (rtPCR). The changes in gene expression induced by each agent were largely distinct; many of the genes significantly modulated by TNF-α were not affected by hemozoin. The genes modulated by TNF-α were significantly enriched for those encoding proteins involved in the control of type 1 interferon signalling and the immune response to viral infection. In contrast, genes induced by hemozoin were significantly enriched for functional roles in regulation of transcription and apoptosis. Further analyses by rtPCR revealed that hemozoin increases expression of transcription factors that form part of the integrated stress response which is accompanied by reduced expression of genes involved in DNA repair. This study confirms that hemozoin induces cellular stress on erythroblasts that is additional to and distinct from responses to inflammatory cytokines and identifies new genes that may be involved in the pathogenesis of severe malarial anemia. More generally the respective transcription profiles highlight the varied mechanisms through which erythropoiesis may be disrupted during infectious disease.
Highlights
Recent efforts to reduce the number of deaths due to malaria have had some success, there is still an estimated 1.2 billion people at high risk of infection worldwide with almost half a million deaths occurring in children
The recently observed elevated levels of hepcidin in patients with acute P. falciparum malaria suggest that the reduced bioavailability of iron contributes to developing severe anemia [6, 7]
These erythroblasts were isolated from cultures derived from different donors and incubated with either 12.5 μg/ml heme equivalents of hemozoin or 10ng/ml TNF-α, doses previously shown to inhibit erythroblasts derived from adult peripheral blood [9, 23]
Summary
Recent efforts to reduce the number of deaths due to malaria have had some success, there is still an estimated 1.2 billion people at high risk of infection worldwide with almost half a million deaths occurring in children. The majority of these infections are due to P. falciparum and P. vivax [1]. Severe malarial anemia is due to increased hemolysis of infected and non-infected red blood cells and to a striking degree of abnormal development of erythroid precursors in acute and chronic infection [8, 9] and an inadequate erythropoietic response in spite of elevated levels of erythropoietin (Epo) [9,10,11]. The distribution of erythroid precursors in the cell-cycle is abnormal with an increased number of cells in the G2 phase compared with normal controls [12, 13]
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