Evolutionary and functional connections between the typhoid toxins encoded by S. Typhi and S. bongori

The virulence properties of numerous important bacterial pathogens have been shaped by the horizontal acquisition of an AB5-type toxin. A major obstacle to the fruitful horizontal transfer of an AB5-type toxin amongst bacteria that infect divergent host species is that these toxins bind specific glycan receptors on target host cells to mediate toxin uptake, and glycosylation patterns vary substantially between different host species. In this study, we explore the evolutionary and functional connections between the related typhoid toxins that are encoded by S. enterica serovar Typhi, a human-adapted pathogen, and by S. bongori, which infects cold-blooded animals. We uncover genetic fingerprints that indicate S. Typhis typhoid toxin islet evolved from a larger virulence islet similar to S. bongoris, and show that S. Typhis glycan-binding PltB subunit is more similar to S. bongori PltB than it is to many diverse PltB sequence variants found in S. enterica. We further show that, surprisingly, S. Typhi strains that encode the S. bongori typhoid toxin islet intoxicate infected human epithelial cells with substantially greater potency than wild-type S. Typhi. The results of this study therefore suggest that the unexpected potency of the S. bongori typhoid toxin toward mammalian cells paved the way for sequence variants derived from this species to be acquired by - and effectively integrated into the virulence program of - the human-adapted pathogen S. Typhi.