Evolution of host adaptation in the Salmonella typhoid toxin
| Autor: | Hai Yu, Lingquan Deng, Xi Chen, Gabrielle Stack, Ajit Varki, Xiang Gao, Yuko Naito-Matsui, Jorge E. Galán |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Male bacterial pathogenesis Cytolethal distending toxin Crystallography X-Ray medicine.disease_cause Applied Microbiology and Biotechnology Salmonella Typhi Virulence factor Mice Models Pathogen Glycomics Crystallography AB5 toxin Adaptation Physiological Medical Microbiology Host adaptation evolution of virulence Microbiology (medical) Virulence Factors Protein subunit Physiological Immunology Bacterial Toxins Virulence Biology Microbiology Article Host Specificity Cell Line 03 medical and health sciences glycobiology Bacterial Proteins Polysaccharides sialylated glycans Genetics medicine Animals Humans Amino Acid Sequence Typhoid Fever Adaptation Binding Sites Toxin Molecular Cell Biology Salmonella typhi N-Acetylneuraminic Acid Endotoxins 030104 developmental biology HEK293 Cells X-Ray Neuraminic Acids Transcription Factors |
| Zdroj: | Nature microbiology, vol 2, iss 12 Nature microbiology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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