Staphylococcus aureus is a globally significant and opportunistic pathogen equipped with a diverse arsenal of virulence factors, including bi-component leukotoxins that play a central role in immune evasion and tissue damage. Despite extensive functional characterization of individual leukotoxins, their diversity, phylogenetic distribution, and evolution remain underexplored. Here, we analyzed 1,779 complete S. aureus genomes to examine six leukotoxin operons: hlgABC, lukED, lukAB, lukSF-PV, lukMF', and lukPQ. Individual genomes carry anywhere between 1 and 4 operons, with 1,123 genomes (63.1%) carrying three operons. Only hlgABC and lukAB were detected at very high frequency (≥99%) and are thus considered core leukotoxins. Based on the different combinations of the six operons, 14 distinct leukotoxin profiles can be distinguished. The 11 sequence types that were most common (ST1, ST5, ST8, ST30, ST45, ST59, ST72, ST105, ST239, ST398, and ST1292) tend to carry one or two unique leukotoxin combinations. Genomes simultaneously carrying hlgABC + lukED + lukAB were common (n = 1,064 genomes). We also identified a genome carrying four copies of lukAB, with evidence of pseudogenization in the three plasmid-borne copies of lukAB. Of the 11 individual leukotoxin genes, lukA, lukB, lukD, hlgB, and hlgC experienced intragenic homologous recombination (all with P lukS, lukF, lukE, and hlgA exhibited Tajima's D Staphylococcus aureus, helping the bacteria evade the host's immune system. These toxins act as lytic molecules that directly target and kill a variety of immune cells. In our study, we show that six leukotoxin operons in S. aureus are combined in different ways within each genome, which may contribute to the pathogen's ability to cause a myriad of diseases and colonize different tissue sites. Understanding the diversity and evolution of different leukotoxin genes will be critical to the development of anti-leukotoxin antibodies and immunization countermeasures that will effectively impede S. aureus infections.
Souza et al. (Mon,) studied this question.