Multiclonal human origin and global expansion of an endemic bacterial pathogen of livestock

Most new pathogens of humans and animals arise via switching events from distinct host species. However, our understanding of the evolutionary and ecological drivers of successful host adaptation, expansion, and dissemination are limited. Staphylococcus aureus is a major bacterial pathogen of humans and a leading cause of mastitis in dairy cows worldwide. Here we trace the evolutionary history of bovine S. aureus using a global dataset of 10,254 S. aureus genomes including 1,896 bovine isolates from 32 countries in 6 continents. We identified 7 major contemporary endemic clones of S. aureus causing bovine mastitis around the world and traced them back to 4 independent host-jump events from humans that occurred up to 2,500 y ago. Individual clones emerged and underwent clonal expansion from the mid-19th to late 20th century coinciding with the commercialization and industrialization of dairy farming, and older lineages have become globally distributed via established cattle trade links. Importantly, we identified lineage-dependent differences in the frequency of host transmission events between humans and cows in both directions revealing high risk clones threatening veterinary and human health. Finally, pangenome network analysis revealed that some bovine S. aureus lineages contained distinct sets of bovine-associated genes, consistent with multiple trajectories to host adaptation via gene acquisition. Taken together, we have dissected the evolutionary history of a major endemic pathogen of livestock providing a comprehensive temporal, geographic, and gene-level perspective of its remarkable success.

The emergence of new pathogens typically arises through host-jump events and is a major threat to public health and food security (1). The domestication of animals and the expansion of agriculture in the Neolithic era increased the opportunities for the zoonotic and anthroponotic transmission of pathogens (2). Subsequent intensification of farming, industrialization, and globalization have increased the likelihood of successful expansion and dissemination of new pathogenic clones. However, our understanding of the evolutionary history of the major bacterial pathogens affecting livestock is very limited. In order to mitigate the emergence of new pathogens, or design novel interventions to limit spread, it is imperative that we understand the evolutionary and ecological drivers for the success of existing pathogens that have originated via host-switching events.S. aureus is a multihost bacterial species and a major pathogen of humans and livestock. In particular, S. aureus is a leading cause of bovine mastitis resulting in huge economic losses to the global dairy industry (3). In addition, bovine S. aureus is recognized as an emergent zoonotic threat (4), but the relative frequency of human infections caused by different clones of bovine S. aureus has not been examined to date. Previously, we demonstrated that the evolution of S. aureus has involved host-switching events between humans and domesticated animals in both directions leading to the emergence of clones circulating in human and livestock populations (5). In addition, we identified gene acquisition as a major driver for the adaptation of S. aureus to a new host species after a host-switch event. However, the limited number of isolates from livestock sources included in the study was insufficient to support analysis of the origin, clonal expansion, and global spread of contemporary livestock clones.Numerous studies have employed whole genome sequencing to explore the diversity of S. aureus from dairy cattle but they have tended to include a limited number of isolates from geographically restricted regions (6–15). In order to address this gap in understanding, we established a genome sequence dataset of 10,254 S. aureus genomes including 1,896 bovine isolates from 32 countries in 6 continents to carry out a comprehensive phylodynamic and accessory genome network analysis. We provide broad insights into the evolutionary origins of bovine S. aureus, including the key impact of human activities, and reveal the adaptive and geographical trajectories that have driven its global success.