Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: Possible role in the pathogenesis of malarial anemia

Human falciparum malaria, caused by Plasmodium falciparum infection, result s in 1 to 2 million deaths per year, mostly children under the age of 5 yea rs. The two main causes of death are severe anemia and cerebral malaria. Ma larial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in t he presence of a robust host erythropoietin response. The production of a h ost-derived erythropoiesis inhibitor in response to parasite products has b een implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1 beta, tumor necrosis factor alpha, and gamma interf eron while injection of interleukin-12 protects susceptible mice against le thal P. chabaudi infection. In this study, we report that ingestion of P. c habaudi-infected erythrocytes or malarial pigment (hemozoin) induces the re lease of macrophage migration inhibitory factor (MIF) from macrophages. MIF , a proinflammatory mediator and counter-regulator of glucocorticoid action , inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-ma crophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correl ated with disease severity. Liver MIF immunoreactivity increased concomitan t with extensive pigment and parasitized RBC deposition. Finally, MIF was e levated three- to fourfold in the spleen and bone marrow of P. chabaudi-inf ected mice with active disease, as compared to early disease, or of uninfec ted controls. In summary, the present results suggest that MIF may be a hos t-derived factor involved in the pathophysiology of malaria anemia.