Structural and functional characterization of a secreted hookworm Macrophage Migration Inhibitory Factor (MIF) that interacts with the human MIF receptor CD74.
Hookworms, parasitic nematodes that infect nearly one billion people worldwide, are a major cause of anemia and malnutrition. We hypothesize that hookworms actively manipulate the host immune response through the production of specific molecules designed to facilitate infection by larval stages and adult worm survival within the intestine. A full-length cDNA encoding a secreted orthologue of the human cytokine, Macrophage Migration Inhibitory Factor (MIF) has been cloned from the hookworm Ancylostoma ceylanicum. Elucidation of the three-dimensional crystal structure of recombinant AceMIF (rAceMIF) revealed an overall structural homology with significant differences in the tautomerase sites of the human and hookworm proteins. The relative bioactivities of human and hookworm MIF proteins were compared using in vitro assays of tautomerase activity, macrophage migration, and binding to MIF receptor CD74. The activity of rAceMIF was not inhibited by the ligand ISO-1, which was previously determined to be an inhibitor of the catalytic site of human MIF. These data define unique immunological, structural, and functional characteristics of AceMIF, thereby establishing the potential for selectively inhibiting the hookworm cytokine as a means of reducing parasite survival and disease pathogenesis.
Cho
Yoonsang
Y
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Jones
Brian F
BF
Vermeire
Jon J
JJ
Leng
Lin
L
DiFedele
Lisa
L
Harrison
Lisa M
LM
Xiong
Huabao
H
Kwong
Yuen-Kwan Amy
YK
Chen
Yibang
Y
Bucala
Richard
R
Lolis
Elias
E
Cappello
Michael
M
D000595:Amino Acid Sequence; D000722:Ancylostoma; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry* / Q000502:physiology*; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008647:Mesocricetus; D008969:Molecular Sequence Data; D011485:Protein Binding; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C045084:invariant chain