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Bacterial pathogens use quorum sensing to regulate the expression of virulence genes as a function of cell density. There is increasing evidence to suggest that enteropathogens can sense host produced neuroendocrine stress hormones as niche-specific environmental cues to regulate the expression of virulence genes. This proposal stems from recent unpublished observations from our laboratories demonstrating the production of signal molecules by Salmonella enterica serovar Typhi and the ability of this pathogen to sense and respond to neuroendocrine stress hormones. <P>
The key goals of the proposal are to:
<OL> <LI> Understand the role of the quorum sensing signal molecules autoinducer-2 and autoinducer-3 in the biology and pathogenicity of S. Typhi. <LI> To purify and chemically characterise the newly discovered autoinducer-3 molecule. To identify the genes and metabolic pathways involved in AI-3 synthesis and in the AI-3 signal transduction system.
<LI> To investigate how the neuroendocrine stress hormones, adrenaline and noradrenaline encountered during infection, can alter the physiology and pathogenicity of S. Typhi, and how these hormones cross-talk with the AI-3 signalling system.</OL> These goals will be achieved using a combination of analytical chemistry, transcriptomics, proteomics, phenotypic screens, and bacterial genetics. <P>
This proposal will provide novel insights in to the combined action of bacterial autoinducers and host-derived hormones on the biology and pathogenicity of S.Typhi. It will provide mechanistic molecular insights of the signal transduction pathways and how these different input signals are sensed and integrated to modulate the virulence and fitness of S.Typhi.<P>
This will fill a significant gap in our knowledge of this under-studied area of research which has major implications in bacterial pathogenicity and the development of novel therapeutics.