Orthologs of macrophage migration inhibitory factor from parasitic nematodes

Abstract

Chronic helminth infections are associated with modulation of host cellular immune responses, presumably to prolong parasite survival within the mammalian host. This phenomenon is attributed, at least in part, to the elaboration of parasite molecules, including orthologs of host cytokines and receptors, at the host-parasite interface. This review describes recent progress in the characterization of macrophage migration inhibitory factor (MIF) orthologs from parasitic nematodes. The roles of these molecules in parasite developmental biology and pathogenesis are discussed. Further knowledge of the species-specific activities and three-dimensional structures of human and parasitic nematode MIF molecules should make them ideal targets for drug- and/or vaccine-based strategies aimed at nematode disease control.

Figure 1

Dendrogram of type-1 and type-2 MIF sequences from across the phylum Nematoda based on amino acid sequence homology. All sequence information was obtained from NCBI GenBank as either translated expressed sequence tags (ESTs) or primary amino acid sequences. GenBank accession numbers for all sequences are listed in Table 1. The dendrogram was generated with Clustalw, and corresponding species clades are shaded by clusters or branches.

Figure 2

Multiple sequence alignments of nematode MIFs. (a) Type 1 MIFs, including prototype CeMIF-1, with corresponding secondary amino acid structure assignments listed above alignment including α-helices represented as red bars, β-strands as yellow arrows and random coils in green. Representative ribbon backbone diagram of type 1 MIF member Trichinella spiralis MIF (TsMIF). (b) Type 2 MIFs, including prototype CeMIF-2, with corresponding secondary amino acid structure assignments as described above. Representative ribbon backbone diagram of type-2 MIF member Ancylostoma ceylanicum MIF (AceMIF). Sequence alignments were generated with Clustalw and BoxShade programs. Identical residues are shaded in black and conserved residues are shaded in gray; residues identical in alignments of all type 1 (21 sequences) or type 2 (14 sequences) MIFs from Table 1 are indicated in the consensus line with a diamond (◇).

Figure 3

Secondary structure and surface presentation of hMIF trimer. Helices (red), strands (yellow) and loops (green) are drawn with the surface of each subunit in different color.

Figure 4

Distinct amino acid composition in the active sites of human and nematode MIFs. The active site residues located within non-covalent interaction distances to the hMIF inhibitor ISO-1 are represented in stick model in each MIF with the corresponding electrostatic surface potential. The crystallographically determined structure of ISO-1 is colored in yellow with hMIF (human MIF) on the left. The active site of TsMIF (Trichinella spiralis) is in the middle with the residues distinct from those of hMIF in cyan. The active site of AceMIF is on the right with the residues distinct from those of hMIF in maroon. The electrostatic surface potential of all the MIFs are scaled equally to each other.

Figure I

Illustration of alternative activation of macrophages and potential mechanism for parasitic nematode-derived, MIF-induced production of AAMΦs [23]. Alternative activation of macrophages is mediated by interleukin-4 (IL-4), IL-13 and possibly IL-21 acting through surface receptors. Characteristic features of AAMΦs include: upregulation of surface receptors including IL-4 receptor (IL-4R), CD-206 (mannose receptor), CD163 (group B scavenger receptor), and MHC II (major histocompatibility class II), among others [54,60]; increased transcription of arginase-1, Ym1/ECF-L (eosinophil chemotactic factor-L), FIZZ1/RELMα (found in inflammatory zone/resistin-like molecule), AMCase (acidic mammalian chitinase) and MMPs (matrix metalloproteinases), among others [53]; modulated expression of cytokines IL-1β, IL-12, IL-10 and transforming growth factor (TGF)- β [4,54]; suppression of T-cell proliferation Th2-type inflammation; and wound repair and eosinophilia [61].