Abstract:

Author summary Salmonella Typhimurium will generally cause acute gut infections in humans. However, S. Typhimurium strains causing severe, systemic infections have emerged in sub-Saharan Africa and are phylogenetically distinct from other S. Typhimurium strains. Our comparative genomic analysis revealed S. Typhimurium sequence-type 313 (ST313) from Africa have notable sequence variations within the macA and macB genes. These genes are already known to play a role in Salmonella pathogenesis and are otherwise conserved in Salmonella and many other Gram-negative bacteria. We show that regulation of macAB transcription depends, in part, on the key Salmonella virulence system PhoP/Q and that expression of MacAB improves Salmonella resistance to an antimicrobial peptide. African macAB variants interfere with this antimicrobial peptide resistance function and can alter Salmonella replication within macrophages. Using competitive infection experiments in mice, we see that these macAB variants influence fitness in the mammalian gut and systemic sites, with African S. Typhimurium reliant upon its macAB genotype for systemic infection of susceptible hosts. These results suggest that the evolution of African S. Typhimurium has been shaped by human populations with impaired ability to control intracellular Salmonella infections.