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Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin

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Abstract

Salmonella enterica serovar Typhi (S. Typhi) differs from most other salmonellae in that it causes a life-threatening systemic infection known as typhoid fever1. The molecular bases for its unique clinical presentation are unknown2. Here we find that the systemic administration of typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of typhoid fever in an animal model. We identify specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of typhoid toxin, which shows an unprecedented A2B5 organization with two covalently linked A subunits non-covalently associated to a pentameric B subunit. The structure provides insight into the toxin’s receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been co-opted into a single, unique toxin that can induce many of the symptoms characteristic of typhoid fever. These findings may lead to the development of potentially life-saving therapeutics against typhoid fever.

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Figure 1: Systemic administration of typhoid toxin causes symptoms observed during the acute phase of typhoid fever.
Figure 2: Typhoid toxin recognizes terminally sialylated glycans on surface glycoproteins.
Figure 3: The crystal structure of typhoid toxin depicts a unique architecture.
Figure 4: Structure-function analysis of typhoid toxin.

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Acknowledgements

We thank members of the Galán laboratory for careful review of this manuscript. We thank E. Folta-Stogniew for help with conducting the surface plasmon resonance and light-scattering size-exclusion chromatography assays. We also thank M. Lara-Tejero and X. Liu for mass spectrometry analysis, J. M. Kim for help with glycan array analysis software, and K.-W. Kim for help in animal inoculations. We thank W. Meng for providing help with X-ray diffraction data collection, J. Wang and C. Yan for suggestions and providing help with structure refinement, and X. Gong and M. Ke for help and suggestions with molecular docking. The glycan array analysis was carried out at the Consortium for Functional Glycomics Protein-Glycan Interaction Core, at Emory University, which is supported by PHS Grant GM098791. J.S. was supported in part by a grant from the Northeast Biodefense Center U54-AI057158 and this work was supported by NIAID Grant AI079022 to J.E.G.

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Contributions

J.S., X.G. and J.E.G. designed the studies and interpreted the results. J.S. and X.G. carried out the experiments. J.S., X.G. and J.E.G. prepared the manuscript.

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Correspondence to Jorge E. Galán.

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The authors declare no competing financial interests.

Additional information

The atomic coordinates have been deposited in the RCSB Protein Data Bank (entry number 4K6L).

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15 and Supplementary Tables 1-4. (PDF 3846 kb)

Symptoms of animals that have received typhoid toxin or buffer control

This video shows the symptoms exhibited by animals that have received typhoid toxin or buffer control. (MOV 1900 kb)

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Song, J., Gao, X. & Galán, J. Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin. Nature 499, 350–354 (2013). https://doi.org/10.1038/nature12377

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