Non-typhoidal salmonellosis (NTS) is responsible of a large proportion of foodborne gastroenteritis worldwide. Molecular identification of Salmonella with assessment of exposure and epidemiological analysis of outbreak-linked cases are main approaches to control NTS. This study focussed on Salmonella Typhimurium (STM) as the most common causative agent of foodborne NTS in Australia. The aims of this thesis were to examine temporal dynamics of STM in New South Wales; to analyse the discrimination power of evolving typing methods for STM and the understanding of within- and between-host variations and adaptations in STM genomes. We examined 11,799 STM isolates between 2009 and 2016. Our findings suggest that multi-locus variable sequence typing (MLST) can be successfully applied for molecular serotyping of Salmonella isolates circulating in NSW. However, its approach lacks discriminatory power for public health surveillance. In contrast, multi-locus variable number tandem repeat analysis (MLVA) identified major clades associated with extensive epidemics over time. A small number of MLVA profiles have been associated with clusters, masking the diversity of profiles and reducing investigations on transmission networks. The sequencing of STM isolates, confirmed the high-resolution and discriminatory power of whole genome sequencing (WGS) elucidating transmission pathways. A relatively constant core genome for STM population over time was revealed, translated in stable diversity with predominance of endemic STM MLVA profiles. A chronic model of salmonellosis in mice showed the adaptive evolution of STM in association within its host. It involved limited number of mutations, without compromising the ability of STM to maintain the infection. The temporal relation between the incidence of STM infections in NSW and the corresponding increase of particular STM clades was unveiled. The comparative genomic analysis performed on STM clades identified genomic polymorphisms within the successful clades. These observations emphasize the stability of accessory genomes, but require further in vivo validation. Our results and analyses have offered evidence to guide the interpretation of STM public health laboratory surveillance and the translation of WGS into more effective control of foodborne diseases
