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Title: The mouse model of trichuriasis : understanding immunity and novel drug development
Author: Murphy, Emma
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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Gastrointestinal helminths infect over 1 billion people worldwide. These parasites rarely cause death but are associated with high levels of morbidity and create large economic burdens where infections are endemic. One parasite in particular, Trichuris trichiura (the human whipworm) infects over 500 million people worldwide and causes morbidity predominantly in children. Trichuris muris, a naturally occurring intestinal parasite of mice has been extensively used as an analogue for the study of immunity T. trichiura. As such, the mouse model is an invaluable tool in dissecting out which components of the immune response to Trichuris infection are important in resistance. Resistance to T. muris infection is tightly associated with the generation of T helper 2 (Th2) immune responses, whereas susceptibility is associated with T helper 1 (Th1) immune responses. Despite a good understanding of the role of T cells in immunity to Trichuris, the involvement of B cells and class switched antibodies in resistance to T. muris infection is still unclear. To determine if class switched antibody has a role in protective immunity against T. muris, two different transgenic mouse models with altered B cell biologies were analysed; the AID knockout mouse (AID-/-) and the IgMi mouse. B cells in both these models have surface bound IgM+ but cannot class switch their immunoglobulin from IgM. Both the AID-/- and the IgMi transgenic mice were significantly less able to expel a primary T. muris infection compared to their C57BL/6 wild type littermates in the absence of class-switched antibody. Lower levels of Th2 cytokines accompanied compromised worm expulsion. When Th1 associated cytokines were blocked in vivo in both transgenic mouse models, efficient worm expulsion occurred. This suggest therefore that protective immunity to a primary T. muris infection does not require secreted parasite-specific antibody per se, but that class-switched antibody on the surface of the B cell, or in the form of immune complexes is necessary for the efficient generation of Th2 mediated immunity. Interestingly, subcutaneous vaccination with worm excretory/secretory antigen in Freund's incomplete adjuvant offered protective immunity in the absence of class switch antibody compared to wild type littermates, albeit delayed. This delayed expulsion also correlated with late development of a Th2 response. Collectively this data supports the conclusion that class switched antibody on the surface of the B cell, or as immune complexes, is important in accessory cell function provided by the B cell in supporting Th2 responses, but when parasite antigen is presented in adjuvant the reliance on B cell accessory function is reduced, and worms are expelled. Effective anti-parasite vaccines must induce high levels of protective immunity in a large proportion of a host population where hosts are genetically heterogeneous. The exact mechanism(s) of protection, required for developing protective immunity post-vaccination, have yet to be identified. There are currently no vaccines available against T. trichiura, and current strategies of helminth control in the field include Mass Drug Administration (MDA) programs during childhood, typically using the benzimidazoles anthelmintics. In the context of Trichuris, the overall efficacy of these drug treatments is reduced after repeated administration, raising concerns about the emergence of resistance to anthelminthic drugs. As current treatments are inadequate, new innovative drugs are urgently needed. In the final chapter of this study, target-free, high-throughput screening was used on a small library of novel chemicals to test their ability to modify parasite behaviour. The measurement of nematode motility by an automated Camera-based Motility Assay was used to directly reflect the activity of the neuromuscular system and indirectly measure the health of the nematode. The data in this study has identified potential anti-helminthic properties of novel compounds shown by the nematode paralysis observed when these compounds are administered to adult worms. This work has also shown the compounds which paralyze adult worms may also be a useful tool to break the T. muris life cycle in the external environment as one novel compound significantly reduced the infectivity of T. muris eggs compared to treating with water or DMSO alone. In summary, these studies have furthered the current knowledge on the contributions of class switched antibodies in the immune response to both primary and post-vaccination infection with T. muris. It suggests that class-switched antibody on the surface of the B cell or in the form of immune complexes, is necessary for the efficient generation of Th2 mediated, protective immunity against Trichuris. Further, preliminary studies using new innovative chemical compounds have identified novel classes of drug-like molecules, which have activity against T. muris, with no compromising toxicity.
Supervisor: Grencis, Richard ; Else, Kathryn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available