Browsing by Author "Smith, Katherine"

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    Cancer cell behaviour following parasite exposure
    (2018) Jacobs, Brittany-Amber; Smith, Katherine; Prince, Sharon
    Infectious diseases, including helminthiases, are estimated to cause 16.1% of global cancer cases. While certain helminths are conclusive causes of cancer, others have been shown to reduce the disease. It is currently unknown why differing helminth infections promote or prevent cancer development and progression, or which cellular mechanisms are altered following exposure. Using several in vitro and in vivo techniques, this study aimed to determine the effect that certain helminths have on the progression of cervical and colorectal cancer. The results revealed that antigen from the hookworm Nippostrongylus brasiliensis significantly reduced cervical cancer cell migration and the expression of two markers of metastasis: vimentin and N-cadherin. Importantly, N. brasiliensis antigen significantly lowered the expression of cell-surface vimentin, while decreasing Human Papillomavirus type16 pseudovirion internalization. In vivo infection with N. brasiliensis significantly decreased vimentin expression within the female genital tract, confirming the relevance of these in vitro findings. Furthermore, exposure to antigen from the gastrointestinal nematode Heligmosomoides polygyrus decreased the in vitro proliferation of human and mouse colorectal cancer cells and simultaneously increased the expression of cell cycle regulator proteins, p53 and p21. Surprisingly, while antigen from H. polygyrus inhibited human colorectal cancer cell migration, it had the opposite effect on mouse colorectal cancer cells, suggesting that its impact on colorectal cancer migration may be, at the very least, species dependent. Using a syngeneic tumour model, the excretory-secretory product from H. polygyrus was shown to significantly increase tumour growth and the expansion of regulatory T cells and neutrophils in the tumour. Similarly, in a model of colitis-associated colorectal cancer this antigen significantly worsened pathology in a TGF-β dependent manner. Undoubtedly, the knowledge gained from this study will contribute to the limited understanding about helminths and the effect that these parasites have on cancer progression.
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    Determining the impact of Heligmosomoides polygyrus infection on the development of colitis
    (2019) Katsandegwaza, Brunette; Smith, Katherine; Horsnell, Bill
    The ability of helminths to regulate inflammatory disorders and the mechanisms by which they carry this out are of great scientific interest. Currently, established literature emphasises the protective role of helminth infection in mouse models of inflammatory bowel disease (IBD). Utilising two well-established murine models of human disease, the oxazolone and dextran sulfate sodium (DSS) models, I found that induction of murine IBD is highly sensitive to diet change and mouse gender. Using the gastrointestinal helminth Heligmosomoides polygyrus (H.polygyrus), I demonstrate that helminth infection exacerbates IBD in both the oxazolone and DSS models of colitis. Underlying helminth infection results in increased inflammation locally in the colon and systemically in the spleen in both models of IBD, as measured by histology and flow cytometry. Exacerbation of DSS colitis is dependent on the dose of H.polygyrus but is independent of the phase of H.polygyrus infection, with both acute and chronic infections resulting in the same phenotype. Helminth exacerbated DSS colitis is characterised by significant bacterial translocation to the spleen, which is concluded to be due to loss of intestinal epithelial integrity. Helminth infection also resulted in a microbial shift of translocating bacteria following DSS administration, as evidenced by gram staining and bacterial sequencing. Administration of an 8- strain probiotic during acute helminth infection ameliorated helminth exacerbation of DSS colitis, restored epithelial integrity and abrogated splenomegaly. This work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive disease. These studies reveal restoration of the microbiota through probiotics or helminth eradication as potential therapies for the treatment of gastrointestinal inflammatory disorders.
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    Surfactant Protein-D is essential for immunity to Helminth Infection
    (Public Library of Science, 2016) Thawer, Sumaiyya; Auret, Jennifer; Schnoeller, Corinna; Chetty, Alisha; Smith, Katherine; Darby, Matthew; Roberts, Luke; Mackay, Rosie-Marie; Whitwell, Harry J; Timms, John F; Madsen, Jens; Selkirk, Murray E; Brombacher, Frank; Clark, Howard William; Horsnell, William G C
    Author Summary Infections by parasitic worms are very common, and controlling them is a major medical and veterinary challenge. Very few drugs exist to treat them, and the parasites can develop resistance to these. In order to find new ways to control worm infections, understanding how our immune system responds to them is essential. Many important parasitic worm infections move through the host lung. In this study we show that a major secreted protein in the lung, Surfactant Protein D (SP-D), is essential for immunity to a parasitic worm infection. We found that this protein binds to worm larvae in the lung to help the immune system kill them. Infecting mice that do not express SP-D with worms demonstrates SP-D is important in this immune response. These mice are unable to launch an effective anti-worm immune response and have many more worms in their intestine compared to mice that do express SP-D. We also show that if we increase SP-D levels in the lung the mouse has better immunity to worms. Together this shows for the first time that SP-D is very important for immunity to worm infections.