Mechanisms of erythropoiesis inhibition by malarial pigment and malaria‐induced proinflammatory mediators in an in vitro model

Abstract

One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.

Maternal Anemia at First Antenatal Visit: Prevalence and Risk Factors in a Malaria-Endemic Area in Benin

“…Plasmodium falciparum directly destroys erythrocytes, 25 but more complex phenomena are also involved, such as the inhibition of erythropoiesis by malarial pigment and malaria-induced pro-inflammatory mediators. 26 Fifteen percent of the women were infected at the first ANV, and 15% of anemic syndromes were attributable to malaria in our population. Such a relatively high prevalence is probably because the women had not been given the first IPTp dose when they were sampled and that for these women, the ANV was care-seeking oriented rather than motivated by a systematic follow-up of pregnancy.…”

Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo

“…29 To date, all of these studies have used GPA or/ and CD71 as indicators of erythroid differentiation stages. However, because temporal changes in the surface expression of GPA and CD71 are not changed substantially during human terminal erythroid differentiation, the use of these markers does not enable optimal separation of human erythroblasts at distinct stages.…”

Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

“…Abnormal erythroid progenitors have been associated with hemozoin-containing myeloid cells in postmortem bone marrow biopsy specimens derived from children with severe malarial anemia (113). The inhibitory role of hemozoin on erythropoiesis has also been characterized using in vitro culture systems showing a direct effect through inhibition of erythroid cell development (114,117), growth inhibition by down-modulation of the expression of several receptors critical for differentiation (117), induction of apoptosis (116), and indirectly through the activity of inflammatory mediators (114). To determine if suppression of erythropoiesis in malarial anemia can be associated with hemozoin deposits in bone marrow, we evaluated the accumulation of hemozoin in the rhesus bone marrow samples using cell image analysis.…”

“…Hemozoin, an insoluble by-product of hemoglobin proteolysis, has been reported to exhibit several biological effects that involve induction of proinflammatory mediators (reviewed in reference 107), dysfunction of monocyte/macrophages (108), modulation of the maturation of dendritic cells (109,110), immunosuppression (111,112), and suppression of erythropoiesis (113)(114)(115)(116)(117). To investigate the role of hemozoin deposition in the pathogenesis of severe malaria, we characterized the relationship between pigment-containing leukocytes, hemoglobin levels, and clinical severity.…”