Abstract
Cytokines are the molecular messengers of the vertebrate immune system, coordinating the local and systemic immune responses to infective organisms. We report here functional and structural data on cytokine-like proteins from a eukaryotic pathogen. Two homologues of the human cytokine macrophage migration inhibitory factor (MIF) have been isolated from the parasitic nematode Brugia malayi. Both molecules (Bm-MIF-1 and Bm-MIF-2) show parallel functions to human MIF. They are chemotactic for human monocytes and activate them to produce IL-8, TNF-alpha, and endogenous MIF. The human and nematode MIF homologues share a tautomerase enzyme activity, which is in each case abolished by the mutation of the N-terminal proline residue. The crystal structure of Bm-MIF-2 at 1.8-A resolution has been determined, revealing a trimeric assembly with an inner pore created by beta-stranded sheets from each subunit. Both biological activity and crystal structure reveal remarkable conservation between a human cytokine and its parasite counterpart despite the considerable phylogenetic divide among these organisms. The strength of the similarity implies that MIF-mediated pathways play an important role in nematode immune evasion strategies.
Highlights
Cytokines are the molecular messengers of the vertebrate immune system, coordinating the local and systemic immune responses to infective organisms
Identification and Cloning of Bm-mif-2 Gene—To date, the Filarial Genome Project has submitted over 20,000 B. malayi expressed sequence tag (EST) representing more than 8,000 different genes [15]
Using protein sequences of human cytokines and their receptors to search this data base, we identified two homologues of the human cytokine migration inhibitory factor (MIF) from B. malayi, one of which was recently reported as Bm-mif [4]
Summary
Vol 277, No 46, Issue of November 15, pp. 44261–44267, 2002 Printed in U.S.A. Homologues of Human Macrophage Migration Inhibitory Factor from a Parasitic Nematode. Two homologues of the human cytokine macrophage migration inhibitory factor (MIF) have been isolated from the parasitic nematode Brugia malayi. Both molecules (BmMIF-1 and Bm-MIF-2) show parallel functions to human MIF. We have used genomic approaches to identify and characterize homologues of the human cytokine macrophage migration inhibitory factor (MIF) from the parasitic nematode Brugia malayi. This parasite is a causative agent of lymphatic filariasis, one of the most important human tropical diseases with an estimated 120 million people infected and an additional 900 million at risk of infection [6]. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY004865
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