title: Ostertagia ostertagi macrophage migration inhibitory factor is present in all developmental stages and may cross-regulate host functions through interaction with the host receptor.
abstract: Macrophage migration inhibitory factor (MIF) of Ostertagia ostertagi, an abomasal parasite of cattle, was characterised in the present study. Phylogenetic analysis identified at least three O. ostertagi MIFs (Oos-MIFs), each encoded by a distinct transcript: Oos-MIF-1.1, Oos-MIF-1.2 and Oos-MIF-2. Oos-MIF-2 is only distantly related to Oos-MIF-1s, but has higher sequence similarity with the Caenorhabditis elegans MIF2. Oos-MIF-1.1 and Oos-MIF-1.2 are similar (93%) and thus collectively referred to as Oos-MIF-1 when characterised with immunoassays. Recombinant Oos-MIF-1.1 (rOos-MIF-1.1) is catalytically active as a tautomerase. A mutation (rOos-MIF-1.1P1G) or duplication of Pro1 residue (rOos-MIF-1.1P1+P) resulted in reduced oligomerisation and loss of tautomerase activity. The tautomerase activity of rOos-MIF-1.1 was only partially inhibited by ISO-1 but was abrogated by a rOos-MIF-1.1-specific antibody. Oos-MIF-1 was detected in all developmental stages of O. ostertagi, with higher levels in the adult stage; it was also detected in adult worm excretory/secretory product. Oos-MIF-1 was localised to the hypodermis/muscle, reproductive tract and intestine, but not to the cuticle. rOos-MIF-1.1, but not rOos-MIF-1.1P1G, was able to specifically bind to human CD74, a MIF cell surface receptor, with an affinity comparable with human MIF. Immunostaining indicated that macrophages were able to internalise rOos-MIF-1.1, further supporting receptor-mediated transportation. Herein we also show that rOos-MIF-1.1 inhibited migration of bovine macrophages and restored glucocorticoid-suppressed, lipopolysaccharide-induced TNF-α and IL-8 in human and/or bovine macrophages. Given its dual role in self-regulation and molecular mimicry, this secreted parasite protein warrants investigation as a vaccine candidate against O. ostertagi infections in cattle.
authors.affiliation: Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA; Shangdong Binzhou Academy of Animal Science and Veterinary Medicine, Binzhou City, Shandong 256600, China.
authors.forename: Guanggang
authors.initials: G
authors.lastname: Qu
authors.affiliation: Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Fetterer
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
authors.forename: Dante
authors.initials: D
authors.lastname: Zarlenga
authors.affiliation: Shangdong Binzhou Academy of Animal Science and Veterinary Medicine, Binzhou City, Shandong 256600, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Shen
authors.affiliation: College of Veterinary Medicine and Animal Science, Jilin University, Changchun, China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA. Electronic address: wenbin.tuo@ars.usda.gov.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Tuo
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D018509:DNA, Helminth / Q000737:chemistry / Q000235:genetics; D020869:Gene Expression Profiling; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010028:Ostertagia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D010802:Phylogeny; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018509:DNA, Helminth; D000949:Histocompatibility Antigens Class II; D016209:Interleukin-8; D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha; C045084:invariant chain
keywords: Cattle; Macrophage migration inhibitory factor; Nematode; Oos-MIF; Ostertagia ostertagi