| First Author | Gao X | Year | 2017 |
| Journal | Nat Microbiol | Volume | 2 |
| Issue | 12 | Pages | 1592-1599 |
| PubMed ID | 28993610 | Mgi Jnum | J:340427 |
| Mgi Id | MGI:7529329 | Doi | 10.1038/s41564-017-0033-2 |
| Citation | Gao X, et al. (2017) Evolution of host adaptation in the Salmonella typhoid toxin. Nat Microbiol 2(12):1592-1599 |
| abstractText | The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host (1-5) . Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi (6,7) , the cause of typhoid fever in humans (8-12) . Typhoid toxin has a unique A(2)B(5) 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 the N-acetylneuraminic acid (Neu5Ac) sialoglycans (6,13) prominently present in humans (14) . Here, we examine the functional and structural relationship between typhoid toxin and ArtAB, an evolutionarily related AB(5) toxin encoded by the broad-host Salmonella Typhimurium (15) . 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 of S. Typhimurium, we found that ArtB binds human glycans, terminated in N-acetylneuraminic acid, as well as glycans terminated in N-glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals (14) . 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. |
