Microbial infection and mechanisms of intestinal inflammation

Wessel, Hannah Margaret (2017) Microbial infection and mechanisms of intestinal inflammation. PhD thesis, University of Glasgow.

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Abstract

The intestinal immune system plays an essential role in maintaining the delicate balance between mounting protective responses against invading pathogens and sustaining tolerance towards self-antigens and the endogenous microbiota. Disturbing this balance leads to intestinal inflammation, such as is seen in inflammatory bowel disease (IBD). IBD is characterised by alterations in the mucosa-associated microbiota, such as the increase in adherent and invasive Escherichia coli (AIEC) species in Crohn’s disease (CD) patients. Concomitantly, the inflamed mucosa exhibits an elevated rate of apoptosis in IBD, a phenomenon that also accompanies infection with a range of enteric bacterial pathogens. While phagocytosis of apoptotic cells by dendritic cells (DC) is required for self-tolerance in the healthy intestine, there is evidence to suggest that apoptotic cell uptake during infection activates protective T cell responses. In order to investigate the link between the recognition of apoptotic cells and intestinal inflammation, we used a range of different in vivo enteric bacterial infection models. Previously published work had implicated the AIEC strain NRG857c in the induction of chronic intestinal inflammation in vivo. We did not, however, find that NRG857c caused any signs of chronic colitis in mice, either by histological examination, or in-depth analysis of both innate and adaptive immune responses in the lamina propria and mesenteric lymph nodes (MLN). Due to the important role of DC in acquiring apoptotic cell antigen and priming protective T cell responses, we next characterised the expression of apoptotic cell receptors, specifically TIM4, on DC populations in steady state mucosal tissues. We demonstrated that TIM4 expression was enriched on CD11b- CD103+ DC, which have previously been shown to cross-present apoptotic cell-derived antigen. However, upon migration in mesenteric lymph, all intestinal DC populations upregulated TIM4, and migratory CD11b+ CD103+ had the highest frequency of TIM4+ cells in the MLN. However, blocking TIM4 did not affect DC migration in vivo. We also found that infection with C. rodentium elevated the percentage of TIM4+ DC in a population-specific manner, but that TIM4 was not essential for the induction of protective T cell responses during infection with either C. rodentium or S. Typhimurium. We therefore provide a detailed analysis of the intestinal immune response to bacterial infection, focussing specifically on the role of the apoptotic cell receptor TIM4 on intestinal DC populations.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Dendritic cell, intestine, microbiota, TIM4, AIEC, apoptosis, infection.
Subjects: Q Science > QR Microbiology
Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Funder's Name: UNSPECIFIED
Supervisor's Name: Milling, Professor Simon W.F. and Wall, Dr. Daniel
Date of Award: 2017
Depositing User: Miss Hannah Margaret Wessel
Unique ID: glathesis:2017-8377
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Sep 2017 15:11
Last Modified: 25 Sep 2017 09:46
URI: http://theses.gla.ac.uk/id/eprint/8377

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