Genomic evolution of <i>Salmonella</i> Dublin in cattle and humans in the United States

Increasingly, antimicrobial-resistant (AMR) <i>Salmonella</i> Dublin is a threat to human and animal health, therefore requiring a One Health approach to comprehensively understand pathogen evolution. Moreover, <i>S</i>. Dublin dissemination throughout the United States and the food supply chain is a concern for food safety and security. Here, we leveraged multi-agency biosurveillance data and genomic sequencing of <i>S</i>. Dublin strains to provide a robust analysis of its evolution across human, animal, and environmental reservoirs. This study advances our understanding of AMR <i>S</i>. Dublin, elucidates factors driving AMR emergence, and informs interventions to protect public health. In total, 2,150 strains collected between 2002 and 2023 throughout the United States from clinical bovine (<i>N</i> = 581), clinical human (<i>N</i> = 664), and environmental (<i>N</i> = 905) sources were identified. After uniform quality control, raw reads were assembled <i>de novo</i> followed by genome annotation and characterization of plasmids, antimicrobial resistance genes, and virulence factors. Strain relatedness was evaluated using a core genome maximum-likelihood phylogeny and pairwise core genome single-nucleotide polymorphism (SNP) differences. We identified the highest prevalence of drug-specific antimicrobial resistance genes and multidrug resistance plasmid, IncA/C2 (<i>P</i> < 0.001), in bovine clinical strains, which also had the greatest genetic diversity. Despite source-dependent differences in antimicrobial resistance gene frequency and types, 72% of <i>S</i>. Dublin strains in our study differed with at least one other strain by 20 or fewer SNPs. This high degree of genomic similarity highlights the potential for cross-transmission between humans, animals, and the environment and underscores the importance of considering strain source when assessing and monitoring antimicrobial resistance.IMPORTANCE<i>Salmonella</i> Dublin is a zoonotic, sometimes foodborne, pathogen that causes severe illness in cattle and humans. Our study takes a One Health approach to understanding genetic differences in strains within and between different reservoirs in the United States. We identified differences in antimicrobial resistance potential and genome content between clinical bovine, clinical human, and environmental strains. Nonetheless, the U.S. population of <i>S</i>. Dublin is highly related and diverges minimally over time and geography. These findings highlight the importance of the One Health framework when combating zoonotic antimicrobial-resistant pathogens like <i>Salmonella</i> Dublin.