Severe malarial
anemia (SMA), caused by Plasmodium falciparum
infections, is one of the leading causes of childhood mortality in sub-Saharan Africa. Although the molecular determinants of SMA are largely undefined, dysregulation in host-derived inflammatory mediators influences disease severity.
Macrophage migration inhibitory factor (MIF) is an important regulator of
innate inflammatory responses that has recently been shown to suppress erythropoiesis and promote pathogenesis of SMA in murine models. To examine the role of MIF in the development of childhood SMA, peripheral blood MIF production was examined in Kenyan children (aged <3 years, n = 357) with P. falciparum malarial
anemia. All children in the study were free from
bacteremia and human immunodeficiency virus type 1. Since deposition of malarial pigment (
hemozoin [Hz]) contributes to suppression of erythropoiesis, the relationship between MIF concentrations and monocytic acquisition of Hz was also examined in vivo and in vitro. Circulating MIF concentrations declined with increasing severity of
anemia and significantly correlated with peripheral blood leukocyte MIF transcripts. However, MIF concentrations in peripheral blood were not significantly associated with reticulocyte production. Multivariate regression analyses, controlling for age, gender, and
parasitemia, further revealed that elevated levels of pigment-containing monocytes (PCM) was associated with SMA and decreased MIF production. In addition, PCM levels were a better predictor of
hemoglobin and MIF concentrations than parasite density. Additional experiments in
malaria-naive individuals demonstrated that
hemozoin caused both increased and decreased MIF production in cultured peripheral blood mononuclear cells (PBMC) in a donor-specific manner, independent of apoptosis. However, PBMC MIF production in children with
acute malaria progressively declined with increasing
anemia severity. Results presented here demonstrate that acquisition of
hemozoin by monocytes is associated with suppression of peripheral blood MIF production and enhanced severity of
anemia in childhood
malaria.