Genomic signatures distinguish isolates of Salmonella Typhimurium from humans and livestock

Salmonella enterica serovar Typhimurium is a major cause of human salmonellosis and livestock represent an important reservoir for human infection through the food chain. However, it remains unclear whether isolates recovered from human disease reflect the broader livestock population or constitute a subset of livestock-associated isolates characterized by specific genetic features. Here, we analysed 1,398 S. Typhimurium genomes from human, poultry, bovine and swine isolates to evaluate whether isolates associated with human disease can be distinguished from those circulating in livestock and to identify the genetic features underlying this discrimination. Whole-genome multilocus sequence typing profiles were converted into a gene presence/absence matrix and analysed using four machine-learning algorithms, which showed high and consistent discriminatory performance. Model performance was influenced by the phylogenetic structure of the population and by the variable distribution of human- and livestock-associated isolates across lineages of sequence type (ST) 19, the most prevalent S. Typhimurium ST. Nevertheless, within ST19, 97 genes were significantly enriched and 36 were significantly depleted in human-associated genomes relative to genomes from each of the three livestock sources. Human-enriched genes included 14 genes required for biosynthesis of the lipopolysaccharide core, the O-antigen, the T1 antigen, and six virulence factors. These genes were consistently absent from livestock-associated genomes across ST19 lineages. Conversely, human-depleted genes included the galactitol utilisation cluster and five virulence genes, which are predominantly absent in specific ST19 lineages. Overall, our findings support the existence of host-associated genomic signatures that distinguish isolates associated with human disease from those sampled from the livestock reservoir.