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Title: Modulation of innate immunity by enteropathogen motifs
Author: Milioris, A. S.
ISNI:       0000 0004 7230 1806
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Bacterial gastroenteritis affects millions, especially in the developing world. While the mechanisms by which enteric pathogens trigger inflammation have been studied extensively, how they evade immune recognition is less understood. We hypothesised that the structural components of common enteric pathogens, such as Clostridium difficile and Campylobacter jejuni, facilitate immune evasion by engaging inhibitory receptors on innate immune cells. In the present study we investigated how C. difficile peptidoglycan (PGN) engages with monocytic cells and identified NOD2 as a critical innate sensor in this interaction. PGN affected cell maturation and in addition it modulated monocytic immune responses to other bacterial motifs, as PGN-exposed cells became unresponsive to subsequent Lipopolysaccharide (LPS) stimulation. This data suggests a role for C. difficile PGNNOD2 axis in trained immunity. We have previously reported on a novel interaction between C. jejuni flagellin pseudaminic acid moieties and the Siglec-10 receptor, an interaction that specifically targets the dendritic cell IL-10 axis. Herein, we studied the downstream signalling events involved in this crosstalk in human macrophages. Utilizing wild-type and isogenic mutant C. jejuni, we identified a potential role for the epidermal growth factor receptor (EGFR), the scaffolding SHP-2 and PI3K-AKT/MAPK kinase pathways in modulating IL-10 expression. We report for the first time novel engagement between C. jejuni 11168H capsule, lipooligosachharide (LOS) and host Siglec-5 and Siglec-9 receptors, pathways involved in bacterial adherence and phagocytosis. Collectively, this thesis provides evidence as to how common bacterial structures exert immunosuppressive effects, effects that may hold the balance between asymptomatic colonization and infection.
Supervisor: Bajaj-Elliott, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available