Frequent host-switch and gene exchange shape the evolution of Staphylococcus aureus ST398

Abstract Staphylococcus aureus ST398 is a typical ‘One Health’ pathobiont exemplifying multiple-host tropisms. Here we traced the evolutionary trajectory of the global accessory genome (an assembly of accessory genes) of S. aureus ST398 over 20 years, with the aim of identifying the mechanisms linking accessory genomes with multiple-host tropisms and the phylogenomic traits associated with severe human infections. We analyzed 1079 high-quality genomes of ST398 from 13 host species, spanning 23 years (1998–2021) and 25 countries across 5 continents, and showed that accessory gene pools of ST398 substantially expanded in the early period before 2010, aligning with the increase in the host-species spectrum. The more recent shifts of accessory genomes were mainly driven by stochastic processes. Accessory genes transferred widely across ST398 from different host-species and barely formed host-specific accessory gene pools, indicating that a host-jump of ST398 was followed shortly by another host-switch rather than a long-term co-evolution with a new host species to generate host-specific gene pools. Human-ST398 was a major recipient of accessory gene transfer, with more common gene transfer with ST398 from pig than other animals. Life-threatening exotoxin genes separately encoding Panton-Valentine Leukocidin and the staphylococcal enterotoxin B were abundant and exclusive to human-ST398 that showed a higher evolution rate than animal-ST398. Both accessory and core genome analyses implied nutrient metabolism as a major force for ST398 evolution. Analyses of clinical data revealed a conserved evolution of ST398 along infection development within a patient, and identified a novel subtype ST398-9 (a relatively recent phylogenetic branch) and phages StauST398_5 and StauST398_1 to be closely associated with human infections. Our findings elucidate mechanisms underlying the distribution and evolution of accessory gene pools of ST398, which determine the development of multiple-host tropisms and pathogenicity.