Quorum Sensing and Host-Pathogen Communication in Salmonella Typhi

Typhoid fever remains a major global health problem and is caused by the foodborne bacterium Salmonella Typhi. We are trying to understand how these bacteria communicate with each other to cause disease. Furthermore, we wish to investigate how Salmonella can eavesdrop on host cell communication for its benefit.

Once Salmonella reach a critical population size, these communication systems enable them to co-ordinately regulate their biological activities and fitness. This allows the bacterial invaders to survive the hostile environment of the human host and invade in critically significant combat numbers to cause Typhoid fever.

The bacterial and host cells communicate using chemical languages. We are trying to determine the chemical identity of the bacterial words used. This knowledge may provide insights into the nature of the cross-talk between Salmonella and the host.

Once bacteria sense these chemical words they produce a synchronised response, ultimately altering their life-style and weaponry to successfully survive and replicate in the human host. We wish to identify the bacterial listening machinery and elucidate the mechanisms by which they respond and orchestrate these activities. Using state-of-the-art technologies we will determine which Salmonella genes and proteins are regulated by the bacterial and host-produced chemical words, and then determine how important these are for the process of infection.

The knowledge gained from this research will allow us to develop new vaccines and anti-infective drugs to control disease.

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This proposal stems from recent unpublished observations from our laboratories demonstrating the production of signal molecules by Salmonella enterica serovar Typhi and the ability of this pathogen to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. The key goals of the proposal are to:
(1) Understand the role of the quorum sensing signal molecules autoinducer-2 and autoinducer-3 in the biology and pathogenicity of S. Typhi.
(2) 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.
(3) 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.
These goals will be achieved using a combination of analytical chemistry, transcriptomics, proteomics, phenotypic screens, and bacterial genetics.

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. 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.