Evolution of host adaptation in the Salmonella typhoid toxin. (December 2017) - Gao, Xiang
Abstract The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host1–5 . Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogenSalmonella Typhi6, 7, the cause of typhoid fever in humans8–12 . Typhoid toxin has a unique A2 B5 architecture with two covalently linked enzymatic 'A' subunits, PltA and CdtB, associated with a homopentameric 'B' subunit made up of PltB, which has binding specificity for theN -acetylneuraminic acid (Neu5Ac) sialoglycans6, 13 prominently present in humans14 . Here, we examine the functional and structural relationship between typhoid toxin and ArtAB, an evolutionarily related AB5 toxin encoded by the broad-hostSalmonella Typhimurium15 . We find that ArtA and ArtB, homologues of PltA and PltB, can form a functional complex with the typhoid toxin CdtB subunit after substitution of a single amino acid in ArtA, while ArtB can form a functional complex with wild-type PltA and CdtB. We also found that, after addition of a single-terminal Cys residue, a CdtB homologue from cytolethal distending toxin can form a functional complex with ArtA and ArtB. In line with the broad host specificity ofS . Typhimurium, we found that ArtB binds human glycans, terminated inN -acetylneuraminic acid, as well as glycans terminated inN -glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals14 . The atomic structure of ArtB bound to its receptor shows the presence of an additional glycan-binding site, which broadens its binding specificity. Despite equivalent toxicity in vitro, we found that the ArtB/PltA/CdtB chimaeric toxin exhibits reduced lethality in an animal model, indicating that the host specialization of typhoid toxin has optimized its targeting mechanisms to the human host. This is a remarkable example of a toxin evolving to broaden its enzymatic activities and adapt to a specific host. Structural illumination of host glycan interaction in the evolution and host adaptation of theSalmonella typhoid toxin.