Evolution of host adaptation in the Salmonella typhoid toxin

Nat Microbiol. 2017 Dec;2(12):1592-1599. doi: 10.1038/s41564-017-0033-2. Epub 2017 Oct 9.

Abstract

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 A2B5 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 AB5 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.

MeSH terms

  • Adaptation, Physiological*
  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / metabolism
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Endotoxins / toxicity*
  • Glycomics
  • HEK293 Cells
  • Host Specificity / drug effects*
  • Host Specificity / physiology*
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • N-Acetylneuraminic Acid / chemistry
  • N-Acetylneuraminic Acid / metabolism
  • Neuraminic Acids / chemistry
  • Neuraminic Acids / metabolism
  • Polysaccharides / metabolism
  • Salmonella typhi / chemistry*
  • Salmonella typhi / pathogenicity
  • Transcription Factors
  • Typhoid Fever / microbiology
  • Virulence Factors

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • CdtB protein, Salmonella typhimurium
  • Endotoxins
  • Neuraminic Acids
  • PltA protein, Salmonella typhimurium
  • Polysaccharides
  • Transcription Factors
  • Virulence Factors
  • cytolethal distending toxin
  • salmonella toxin
  • N-glycolylneuraminic acid
  • N-Acetylneuraminic Acid