A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia.
The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379-385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279-281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and gamma interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.
McDevitt
Michael A
MA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mmcdevi1@jhmi.edu
Xie
Jianlin
J
Ganapathy-Kanniappan
Shanmugasundaram
S
Shanmugasundaram
Ganapathy
G
Griffith
Jason
J
Liu
Aihua
A
McDonald
Courtney
C
Thuma
Philip
P
Gordeuk
Victor R
VR
Metz
Christine N
CN
Mitchell
Robert
R
Keefer
Jeffrey
J
David
John
J
Leng
Lin
L
Bucala
Richard
R
D000483:Alleles; D000740:Anemia / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines; D015672:Erythroid Precursor Cells / Q000276:immunology; D004920:Erythropoiesis / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006420:Hemeproteins / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage / Q000172:deficiency / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008288:Malaria / Q000150:complications / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016788:Plasmodium chabaudi / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D006420:Hemeproteins; D008263:Macrophage Migration-Inhibitory Factors; C020753:hemozoin; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse