title: MIF-Mediated Hemodilution Promotes Pathogenic Anemia in Experimental African Trypanosomosis.
abstract: Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, which hampers the development of an effective therapy. Here, the contribution of the erythropoietic and erythrophagocytic potential as well as of hemodilution to the development of T. congolense-induced anemia were addressed in a mouse model of low virulence relevant for bovine trypanosomosis. We show that in infected mice, splenic extramedullary erythropoiesis could compensate for the chronic low-grade type I inflammation-induced phagocytosis of senescent red blood cells (RBCs) in spleen and liver myeloid cells, as well as for the impaired maturation of RBCs occurring in the bone marrow and spleen. Rather, anemia resulted from hemodilution. Our data also suggest that the heme catabolism subsequent to sustained erythrophagocytosis resulted in iron accumulation in tissue and hyperbilirubinemia. Moreover, hypoalbuminemia, potentially resulting from hemodilution and liver injury in infected mice, impaired the elimination of toxic circulating molecules like bilirubin. Hemodilutional thrombocytopenia also coincided with impaired coagulation. Combined, these effects could elicit multiple organ failure and uncontrolled bleeding thus reduce the survival of infected mice. MIF (macrophage migrating inhibitory factor), a potential pathogenic molecule in African trypanosomosis, was found herein to promote erythrophagocytosis, to block extramedullary erythropoiesis and RBC maturation, and to trigger hemodilution. Hence, these data prompt considering MIF as a potential target for treatment of natural bovine trypanosomosis.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Benoît
authors.initials: B
authors.lastname: Stijlemans
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Lea
authors.initials: L
authors.lastname: Brys
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: VIB Vesalius Research Center, University of Leuven (KUL), Leuven, Belgium.
authors.forename: Pawel
authors.initials: P
authors.lastname: Bieniasz-Krzywiec
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sparkes
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Liese
authors.initials: L
authors.lastname: Vansintjan
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Laboratorium Cellulaire Genetica (CEGE), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Vanbekbergen
authors.affiliation: VIB Vesalius Research Center, University of Leuven (KUL), Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Wilrijk, Belgium.|Unit of Veterinary Protozoology, Department of Biomedical Sciences, Institute of Tropical Medicine Antwerp (ITM), Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Caljon
authors.affiliation: Unit of Veterinary Protozoology, Department of Biomedical Sciences, Institute of Tropical Medicine Antwerp (ITM), Antwerp, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Den Abbeele
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Department of Structural Biology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Odongo
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Department of Structural Biology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Carl
authors.initials: C
authors.lastname: De Trez
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Department of Structural Biology, Vrije Universiteit Brussel, Brussels, Belgium.|Laboratory for Biomedical Research, Ghent University Global Campus, Yeonsu-Gu, Incheon, South Korea.
authors.forename: Stefan
authors.initials: S
authors.lastname: Magez
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Lab of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D002417:Cattle; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D004920:Erythropoiesis; D006411:Hematopoiesis, Extramedullary; D006438:Hemodilution; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D014348:Trypanosoma congolense / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse