Acquistion and selection of virulence traits of Salmonella enterica serovar Typhimurium in the organs of infected mice

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Salmonella enterica is a pathogen capable of causing a spectrum of diseases in humans and animals. S. enterica serovar Typhi causes approximately 22 million cases of typhoid fever and over 200,000 deaths annually; serovar Paratyphi causes about 5.5 million annual cases in humans. Other non-typhoidal Salmonella serotypes (NTS) cause gastroenteritis in humans and animals and can spread from animals to humans via contaminated food (e.g. meat and eggs). NTS are a common cause of bacteraemia and sepsis in immuno-compromised individuals (e.g. HIV and malaria patients) and in children, especially in developing countries (e.g. Africa), where they constitute a major cause of death. Current measures in the treatment of S. enterica infections have been revealed as insufficiently effective, and there is a need to develop novel vaccines and therapeutics. The interaction between S. enterica with the host immune system is complex and the outcome of the infection is the result of a fine balance between a continuous escalation of the immune response and the expression of bacterial immunoevasion mechanisms. Consequently, in order to continue growing in the tissues, S. enterica is likely to require the coordinated and sequential regulation of genes. Bacterial gene regulation has so far been investigated largely using exposure to artificial environmental conditions or to in vitro cultured cells and little information is available on how S. enterica adapts in vivo to sustain cell division and survival. Currently, it is impossible to mimic in vitro the many, possibly unknown, inflammatory events that occur during infection. Understanding how gene regulation affects virulence traits of bacterial pathogens in vivo is one of the major challenges of the post-genomic era. Using microbiology, microscopy and sensitive molecular techniques we aim to develop an understanding of the dynamic interactions between host and bacterial mechanisms that determine net growth rates of S. enterica within the host. These experiments will help us to develop an understanding of the influence of passage in a host on the fitness and virulence of S. enterica, which will directly inform the development of novel vaccines and strategies to control and treat a major global health problem.