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Trichuris trichiura is a parasite that infects 500 million people worldwide, leading to colitis, growth retardation and Trichuris dysentery syndrome. There are no licensed vaccines available to prevent Trichuris infection and current treatments are of limited efficacy. Trichuris infections are linked to poverty, reducing children's educational performance and the economic productivity of adults. We employed a systematic, multi-stage process to identify a candidate vaccine against trichuriasis based on the incorporation of selected T-cell epitopes into virus-like particles. We conducted a systematic review to identify the most appropriate in silico prediction tools to predict histocompatibility complex class II (MHC-II) molecule T-cell epitopes. These tools were used to identify candidate MHC-II epitopes from predicted ORFs in the Trichuris genome, selected using inclusion and exclusion criteria. Selected epitopes were incorporated into Hepatitis B core antigen virus-like particles (VLPs). Bone marrow-derived dendritic cells and bone marrow-derived macrophages responded in vitro to VLPs irrespective of whether the VLP also included T-cell epitopes. The VLPs were internalized and co-localized in the antigen presenting cell lysosomes. Upon challenge infection, mice vaccinated with the VLPs+T-cell epitopes showed a significantly reduced worm burden, and mounted Trichuris-specific IgM and IgG2c antibody responses. The protection of mice by VLPs+T-cell epitopes was characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines and goblet cell hyperplasia. Collectively our data establishes that a combination of in silico genome-based CD4+ T-cell epitope prediction, combined with VLP delivery, offers a promising pipeline for the development of an effective, safe and affordable helminth vaccine.

Helminth parasites are complex multicellular organisms capable of maintaining long lasting, chronic infections in human hosts. To ensure their survival and successful reproduction, helminth parasites have developed immunomodulatory mechanisms to modulate their host’s immune system to minimise the physical and immunological pathology to the host and prevent parasite expulsion. Many cells of the immune system are targets for parasite mediated immune modulation including T cells, macrophages and dendritic cells. Further, many inflammatory diseases feature an imbalance between the main subsets of macrophages, M1 and M2, in favour of the M1 pro-inflammatory phenotype. Also, many helminth products have been shown to be able to skew immune responses away from M1 macrophages, thus potentially attenuating disease progression. Therefore, the excretory/secretory products (ES) of the adult stage of the gastrointestinal nematode parasite Trichuris muris have been studied to explore their potential to modulate macrophage biology. Bone marrow derived macrophages (BMDM) were selected to (a) evaluate the ability of T. muris ES to down regulate pro-inflammatory macrophage responses; (b) explore the intracellular mechanisms underlying any immunomodulatory activity and (c) assess the potential of ES molecules to confer protection from inflammatory and autoimmune disorders.Pre-treatment of murine BMDMs with T. muris ES and its fractions significantly suppressed the expression of the pro-inflammatory mediators TNF, IL-27, CCL2, IL-6, IL-Iβ, and Nos2 upon LPS stimulation. T. muris ES also reduced the phosphorylation of p65 at serine 536, downregulated the expression of the histone acetyl transferase (HAT) p300 family, and upregulated the expression of histone deacetylases (HDACs). Moreover, bone marrow cells differentiated to BMDM in the presence of T. muris ES reduced the inflammatory responses of the mature BMDM through modifying the expression of the epigenetic enzymes (HATs and HDACs), with these effects of ES being reversed by epigenetic inhibitors. ES also increased the expression of macrophage cell surface markers on differentiated BMDMs. T. muris ES suppressed multiple LPS-driven genes in the TLR signalling pathway of both murine BMDM pre-incubated with ES, and BMDM derived from ES-exposed bone marrow cells. Ingenuity pathway analyses suggested the involvement of intracellular pathway regulators that orchestrate the expression of the inflammatory genes. Thus, T. muris ES has the potential to limit the pathology associated with inflammatory and autoimmune diseases.

Helminth parasites are complex multicellular organisms capable of maintaining long lasting, chronic infections in human hosts. To ensure their survival and successful reproduction, helminth parasites have developed immunomodulatory mechanisms to modulate their host’s immune system to minimise the physical and immunological pathology to the host and prevent parasite expulsion. Many cells of the immune system are targets for parasite mediated immune modulation including T cells, macrophages and dendritic cells. Further, many inflammatory diseases feature an imbalance between the main subsets of macrophages, M1 and M2, in favour of the M1 pro-inflammatory phenotype. Also, many helminth products have been shown to be able to skew immune responses away from M1 macrophages, thus potentially attenuating disease progression. Therefore, the excretory/secretory products (ES) of the adult stage of the gastrointestinal nematode parasite Trichuris muris have been studied to explore their potential to modulate macrophage biology. Bone marrow derived macrophages (BMDM) were selected to (a) evaluate the ability of T. muris ES to down regulate pro-inflammatory macrophage responses; (b) explore the intracellular mechanisms underlying any immunomodulatory activity and (c) assess the potential of ES molecules to confer protection from inflammatory and autoimmune disorders. Pre-treatment of murine BMDMs with T. muris ES and its fractions significantly suppressed the expression of the pro-inflammatory mediators TNF, IL-27, CCL2, IL-6, IL-Iβ, and Nos2 upon LPS stimulation. T. muris ES also reduced the phosphorylation of p65 at serine 536, downregulated the expression of the histone acetyl transferase (HAT) p300 family, and upregulated the expression of histone deacetylases (HDACs). Moreover, bone marrow cells differentiated to BMDM in the presence of T. muris ES reduced the inflammatory responses of the mature BMDM through modifying the expression of the epigenetic enzymes (HATs and HDACs), with these effects of ES being reversed by epigenetic inhibitors. ES also increased the expression of macrophage cell surface markers on differentiated BMDMs. T. muris ES suppressed multiple LPS-driven genes in the TLR signalling pathway of both murine BMDM pre-incubated with ES, and BMDM derived from ES-exposed bone marrow cells. Ingenuity pathway analyses suggested the involvement of intracellular pathway regulators that orchestrate the expression of the inflammatory genes. Thus, T. muris ES has the potential to limit the pathology associated with inflammatory and autoimmune diseases.