Alternate subunit assembly diversifies the function of a bacterial toxin

Abstract Bacterial toxins with an AB5 architecture are central to bacterial pathogenesis. Functionally diverse and evolutionarily distant AB5 toxins adopt synonymous structures in which a discrete domain of the toxin’s active (A) subunit is inserted into a ring-like platform comprised of five delivery (B) subunits. Salmonella Typhi, the cause of typhoid fever, produces an unusual A2B5 toxin known as typhoid toxin, a major virulence factor. Here, we report that upon infection of human cells, S. Typhi produces two forms of typhoid toxin that have distinct delivery components but share common active subunits. We demonstrate that the two typhoid toxins exhibit substantially different trafficking properties, elicit markedly different effects when administered to laboratory animals, and are expressed in response to different regulatory mechanisms and distinct metabolic cues. Collectively, these results indicate that the evolution of two typhoid toxin variants has conferred functional versatility to this virulence factor. More broadly, this study reveals a new paradigm in toxin biology and suggests that the evolutionary expansion of AB5 toxins was likely fueled by the remarkable plasticity inherent to their structural design coupled to the functional versatility afforded by the combination of homologous toxin components.