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Title: Characterising the innate and adaptive immune response to intestinal helminth infection
Author: Lawrence, Emma
ISNI:       0000 0004 2729 5427
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Gastrointestinal parasites are one of the most prevalent infections known to infect mammals, estimated to affect over one billion people globally. It is well established that the generation of a type two response, characterised by CD4+ T cell secretion of interleukin (IL)-13, IL-4 and IL-9 will expel most gastrointestinal helminths. Expulsion is mediated by a variety of effector mechanisms including altered mucin production, intestinal mast cell activation, increased epithelial cell turnover and increased muscle contraction. Protective immunity can be generated over time; however, infections can persist to chronicity following the modulation of a protective type two response, such as the generation of a type one response. This response, characterised by IFN-γ and IL 12 secretion, can lead to long lived infections, placing huge morbidity upon infected individuals. The mechanisms leading to the generation of a type one or type two response are not fully understood and are of paramount importance if a vaccine to helminth parasites is to be developed. In addition, the dysregulation of these responses is thought to be the cause of allergy and autoimmunity and understanding the regulation of type two responses will also add to our understanding of these diseases.Numerous labs have recently reported roles for new innate cells, such as nuocytes, as sources of IL 13, a cytokine critical to worm expulsion. In addition, data from this lab have demonstrated that NK cell derived IL-13 is the cause of pathology during infection with Trichinella spiralis. It has also been shown that NK cells provide a supplementary source of IL-13 in Trichuris muris infected IL-4-/- mice. This thesis has used 2 strains of mice; the E4bp4-/- mouse and the Il13eGFP reporter mouse, in order to dissect the role of innate cells in the immune response to the related helminth parasites T. muris and T. spiralis. The transcription factor E4BP4 has been shown to control CD4+ T cell IL-5 and 13 secretion and the development of NK cells. Data presented in this thesis show that following a low dose infection, which usually persists to chronicity in WT mice, E4bp4-/- mice were able to expel the parasite following the generation of an elevated type two response. This effect was abrogated following CD4+ T cell depletion, indicative of an essential role for these cells in this response. It was also shown that E4BP4 ablation was sufficient to delay expulsion of a high dose of T. muris, indicative of a key role for E4BP4 in regulating type two responses to T. muris. Contrary to the hypothesis, it was demonstrated that NK cells did not play a major role in protective immunity to T. muris.In addition, the data presented here show, for the first time, the induction of nuocytes in the MLN following both T. muris and T. spiralis infection. Nuocytes made an early contribution to IL-13 secretion following T. spiralis infection; whereas low levels of Il13eGFP+ cells were observed only at day 18-21 post T. muris infection, with nuocytes making a less significant contribution to IL-13 levels. The levels of different cell lineages in the MLN post infection and their contribution to IL-13 expression was also mapped in detail.Finally, an analysis of the haematopoietic response in the bone marrow following T. muris infection was undertaken. The percentage and number of early progenitor Lineage-Sca-1+c-kit+ (LSK) cells in the bone marrow increased at day 21 post T. muris infection. LSK levels returned to normal after this time, indicative of an inflammation dependent response. Interestingly, E4bp4 ablation abrogated this effect, in line with the hypothesised role of IFN-γ in this expansion. Taken together, these data have added to our knowledge of the orchestration of immune responses to two intestinal helminth parasites; T. muris and T. spiralis.
Supervisor: Grencis, Richard; Else, Kathryn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available