Characterisation of an immune-modulating peptide secreted by a helminth worm
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Parasitic worms (helminths) have evolved mechanisms to potently modulate the mammalian immune response to ensure their long-term survival, while concomitantly preventing excessive tissue pathology within the host. The outcome of this activity is a potent suppression of mammalian pro-inflammatory Th1 and Th17 immune responses. This immune-modulatory phenomenon is attributable to the molecules excreted/secreted by helminths as they migrate through their human hosts. The identification of these molecules has the potential to contribute to the development of novel therapeutics for the treatment of autoimmune diseases as these diseases are mediated by pro-inflammatory Th1 and Th17 immune responses. It has previously been shown that the delivery of a single peptide, FhHDM-1, which is excreted/secreted from the helminth, Fasciola hepatica, prevented the development of murine type 1 diabetes and multiple sclerosis. The aetiological similarity between these two diseases, is the establishment of the pro-inflammatory environment by macrophages and neutrophils. Therefore, it was hypothesised that FhHDM-1 likely mediated its protective effect through anti-inflammatory mechanisms directed at these cells. In this study, it was confirmed that FhHDM-1, specifically interacted with both murine and human neutrophils and macrophages. Furthermore, it was demonstrated that FhHDM-1 modulated the activity of these cells, by inhibiting the secretion of pro-inflammatory cytokines/chemokines, which, in turn, prevented further activation of pro-inflammatory T cells and dendritic cells. The use of transcriptional profiling revealed that, of the 41,436 genes analysed in macrophages, treatment with FhHDM-1 altered the expression levels of only 6 of these. Of these, only the expression level of SerpinB2 was increased, and this was shown to subsequently mediate the suppression of pro-inflammatory cytokine secretion by T cells. In the context of an inflammatory stimulus, FhHDM-1 regulated the expression of numerous pro-inflammatory genes in macrophages. Pathway analysis predicted that this anti-inflammatory activity was mediated through the activation of PPAR-γ pathways. This is the first report of a PPAR-γ agonist being secreted by a helminth parasite as a mechanism of modulating mammalian innate immune responses. Importantly, a homologous parasite peptide from a related trematode parasite demonstrated the same activity suggesting a conserved mechanism of action among parasite helminths. Analysis of the sequence of the FhHDM-1 peptide, combined with immunological assays of peptide derivatives, supported the discovery of the minimally active sequence, FhHDM-1.C2. This peptide contained both the amphipathic C-terminus region, previously identified as functional, and a sequence of 5 amino acids (KARDR), which was newly identified as essential for the binding and internal localisation of FhHDM-1. This C2 derivative mimicked the activity of the full length peptide in every way, such as the ability to bind and be internalised by macrophages, to increase macrophage lysosomal pH, to induce the expression of SerpinB2, and to inhibit the production of pro-inflammatory cytokines. In summary, this thesis has newly identified the binding and active domains of the parasite immune-modulatory peptide, FhHDM-1, and discovered the novel mechanisms by which the peptide regulates pro-inflammatory innate immune responses. Combined, these findings have significantly advanced the progress towards translation of the FhHDM-1 peptide for therapeutic use in immune-mediated diseases.
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