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Infection and Immunity, April 2000, p. 2259-2267, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Macrophage Migration Inhibitory Factor Release by Macrophages after Ingestion of Plasmodium chabaudi-Infected Erythrocytes: Possible Role in the Pathogenesis of Malarial Anemia

James A. Martiney,1,* Barbara Sherry,1 Christine N. Metz,2 Marisol Espinoza,1 Angel S. Ferrer,1 Thierry Calandra,2,dagger Hal E. Broxmeyer,3 and Richard Bucala2

Laboratory of Cytokine Biology1 and Laboratory of Medical Biochemistry,2 The Picower Institute for Medical Research, Manhasset, New York 11030, and Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 462023

Received 24 August 1999/Returned for modification 7 October 1999/Accepted 13 January 2000

Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1beta , tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudi infection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release 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-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three- to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia.

* Corresponding author. Mailing address: Forchheimer 520 Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2048. Fax: (718) 430-2140. E-mail: martiney{at}freewweb.com.

dagger Present address: Division of Infectious Diseases, Department of Internal Medicine, BH-19.111, CHUV, CH-1011 Lausanne, Switzerland.

Infection and Immunity, April 2000, p. 2259-2267, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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