Macrophage-migration Inhibitory Factor (MIF) homologues in the host-parasite interaction.

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