In Pseudomonas aeruginosa, which causes severe secondary infections in immunocompromised patients, virulence factor expression is regulated by quorum sensing signal molecules known as acyl homoserine lactones (AHLs). One of the major AHLs produced by P. aeruginosa, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), has also been shown to alter the function of a range of mammalian cells. The goals of experiments reported in this thesis were to use murine models to investigate the effects of in vivo exposure to OdDHL on TH responses, define the direct effects of OdDHL on TH cells and to explore the mechanism by which OdDHL alters the function of TH cells. It was found that in vivo exposure to OdDHL led to changes in cytokine and antibody subclass production indicative of a shift towards the underlying TH bias of the mouse strain studied. Such shifts may play a role in infections with P. aeruginosa, as strong TH1 or TH2 responses have been associated with worsening prognosis for the host, while more balanced responses have been associated with decreases in both infection and pathology. These results suggest that treatments targeting the immunomodulatory activities of OdDHL may be of benefit in the clinical setting in the future. Direct analysis of TH cells in defined in vitro systems revealed that exposure to OdDHL led to uniform decreases in cytokine production and proliferation. These decreases in cytokine production were found to be the result of OdDHL acting on both TH cells and the antigen presenting cells (APCs) that activate them, and only occurred when cells were exposed to OdDHL within 4 hours of stimulation. These findings suggest that OdDHL is acting on a molecular target common to several cells types, and that in TH cells and APCs, this target is involved in the early stages of TH cell activation. Experiments in which T cells were activated with mitogens that bypass the cell membrane revealed that OdDHL is not acting on the cell membrane or membrane-associated activation factors, suggesting that OdDHL is instead inhibiting TH cell function through interactions with one or more intracellular signalling molecules.
| Identifer | oai:union.ndltd.org:ADTP/187966 |
| Date | January 2005 |
| Creators | Ritchie, Adam John, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW |
| Publisher | Awarded by:University of New South Wales. Biotechnology and Biomolecular Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Adam John Ritchie, http://unsworks.unsw.edu.au/copyright |
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