Distinguishable epidemics of multidrug-resistant Salmonella Typhimurium DT104 in different hosts

Abstract

The global epidemic of multidrug-resistant Salmonella Typhimurium DT104 provides an important example, both in terms of the agent and its resistance, of a widely disseminated zoonotic pathogen. Here, with an unprecedented national collection of isolates collected contemporaneously from humans and animals and including a sample of internationally derived isolates, we have used whole-genome sequencing to dissect the phylogenetic associations of the bacterium and its antimicrobial resistance genes through the course of an epidemic. Contrary to current tenets supporting a single homogeneous epidemic, we demonstrate that the bacterium and its resistance genes were largely maintained within animal and human populations separately and that there was limited transmission, in either direction. We also show considerable variation in the resistance profiles, in contrast to the largely stable bacterial core genome, which emphasizes the critical importance of integrated genotypic data sets in understanding the ecology of bacterial zoonoses and antimicrobial resistance.

Fig. 1. Phylogeny of Scottish and global Salmonella Typhimurium DT104, rooted on S. Typhimurium SL1344.

Colored rings indicate, from the center out, the host and country of origin, and the unique genotypic antimicrobial resistance profiles of each isolate (Table S6); the asterisk indicates the location of the reference isolate HF937208. The same tree with bootstrap values added is shown in Fig. S5.

Fig. 2. Bayesian maximum clade credibility phylogenetic tree and most probable ancestral state reconstruction of host population for Salmonella Typhimurium DT104 in Scotland.

A) Branches with a reconstructed state (host population) posterior probability > 0.75 are colored red for human, blue for animal; branches with a state probability < 0.75 are colored grey. The same tree is shown in Fig. S6, with branch width scaled by the posterior probabilities. B) Posterior density plot of the numbers of human branches ancestral to human branches, human branches ancestral to animal branches, animal branches ancestral to human branches, and animal branches ancestral to animal branches integrated over the subsample of 3,600 phylogenetic trees with reconstructed host population states along branches obtained using BEAST. These results suggest 1) circulation of DT104 predominantly within animals and humans separately, with only a low frequency of spill-over in both directions, and/or or 2) animals and humans were each sinks for different and separate sources of infection, with only a low frequency of spill-over in both directions.

Fig. 3. Venn diagrams demonstrating the degree of overlap in antimicrobial resistance (AMR) between the human and animal populations of S. Typhimurium DT104.

A) The numbers of shared and unique AMR determinants (acquired resistance genes or single nucleotide polymorphisms known to confer resistance) in the 147 Scottish human and animal DT104 isolates investigated for AMR diversity; B) The numbers of shared and unique AMR profiles (unique combinations of AMR determinants) in the 147 isolates; C) The numbers of shared and unique AMR phenotypic profiles (unique combinations of AMR phenotypes) in the original 5,200 surveillance isolates of DT104, 1990-2004, Scotland (11); D) Rarefaction curves, with 95% confidence intervals (vertical lines), of the number of genotypic AMR profiles in the 147 isolates investigated for AMR diversity, demonstrating similar sampling intensity.