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The ability of filarial parasites to persist in an immunological competent host, has led to the suggestion that they have evolved specific measures to counter immune defences. Filarial nematodes produce and secrete excretory-secretory (ES) products, some of which have been described to have a potential role in immune evasion. As part of these ES products, two homologues of the mammalian cytokine macrophage-migration inhibitory factor (MIF) have been described from the filarial nematode Brugia malayi, Bm-MIF-1 and Bm-MIF-2. Mammalian MIF is a widely distributed protein constitutively expressed in many immune and non-immune cell types. Although firstly characterised by its ability to stop migration of peritoneal macrophages, it has now been shown to play an important role during different inflammation processes. The main aim of this study is to elucidate the role of Brugia MIF homologues and their relation with the mammalian cytokine. This thesis studies the effect of both filarial and host MIF homologues on two major immune cell types, macrophages and dendritic cells (DC). We found that both Brugia and mouse-MIF synergise with IL-4 to activate macrophages to an alternative phenotype, by enhancing expression of IL-4-induced alternative activation markers Arginase-1, Ym-1 and the macrophage Mannose Receptor. MIF also synergises with IL-4 to render macrophages suppressive, an important outcome during filarial infection. Additionally we found that MIF homologues induce IL-4Ra expression, suggesting a mechanism by which MIF enhances IL-4 activation. We showed that filarial and mouse MIF homologues differ in their capacity to activate bone marrow-derived immature dendritic cells. Mouse-MIF up-regulates MHC-II and CD40 expression and induces pro-inflammatory cytokine production after overnight treatment. On the other hand Bm-MIF-2 induces low levels of cytokine production but does not up-regulate activation markers, and Bm-MIF-1 failed to activate DC. Furthermore, we demonstrate that filarial MIF homologues impair DC differentiation from bone marrow precursors. While bone marrow cells cultured in the presence of GM-CSF, with or without mouse-MIF, differentiate into CD11c+ DC, addition of Bm-MIF-2 to the culture media impairs differentiation arresting the cells in an undifferentiated phenotype characterised by the expression of myeloid and granulocyte markers CD11b and GR1. Finally, using an in vivo model where we implant Brugia malayi parasites in the peritoneal cavity of mice, we observed that host MIF does not play an essential role in the activation of macrophages by adult parasites as macrophages form MIF deficient mice present the same phenotype as their wild type counterparts.

Nematoda is a very diverse animal phylum. Within Nematoda, species display a multitude of life styles, different reproductive strategies and parasitism has arisen independently several times. Furthermore, morphological conservation and a high rate of homoplasy have impeded the resolution of nematode systematics. To address these issues, single gene (usually the nuclear ribosomal small subunit gene) and mitochondrial gene phylogenies have been used, but the information contained within the sequence of these genes is not enough to resolve the topological relationships between clades that emerged during rapid cladogenesis. Next generation sequencing data have been shown to produce high quality genomic and transcriptomic assemblies at low cost, as a result more and more nematode species are being sequenced. Sequences were gathered or generated for 53 nematode species from ESTs, gene predictions from full genome assemblies and transcripts from RNA-Seq experiments. These sequences were screened for orthologous gene clusters, which were concatenated into a supermatrix with thousands of aminoacid sites. The analysis of the supermatrix with maximum likelihood and Bayesian inference methods sheds light into the early splitting clades of the phylogenetic tree of nematodes and the derived clades III, IV and V. Furthermore, the phylogenetic relationships within the parastitic family Onchocercidae were resolved, unveiling the evolutionary history of these important taxa. Finally, data produced in this work will be useful for subsequent evolutionary studies of the phylum Nematoda.

M.Sc. (Nematology) / Please refer to full text to view abstract

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Thesis (MSc. (Veterinary Tropical Diseases)--University of Pretoria, 2009. / Includes bibliographical references. Also available in print format.