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Nat Microbiol. 2018 Feb;3(2):155-163. doi: 10.1038/s41564-017-0076-4. Epub 2017 Dec 4.

In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor.

Author information

1
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
2
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, USA.
3
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
4
Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, USA.
5
Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
7
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA. jeongmin.song@cornell.edu.

Abstract

Typhoid fever is a life-threatening disease, but little is known about the molecular bases for its unique clinical presentation. Typhoid toxin, a unique virulence factor of Salmonella Typhi (the cause of typhoid fever), recapitulates in an animal model many symptoms of typhoid fever. Typhoid toxin binding to its glycan receptor Neu5Ac is central, but, due to the ubiquity of Neu5Ac, how typhoid toxin causes specific symptoms remains elusive. Here we show that typhoid toxin displays in vivo tropism to cells expressing multiantennal glycoprotein receptors, particularly on endothelial cells of arterioles in the brain and immune cells, which is in line with typhoid symptoms. Neu5Ac displayed by multiantennal N-glycans, rather than a single Neu5Ac, appears to serve as the high-affinity receptor, as typhoid toxin possesses five identical binding pockets per toxin. Human counterparts also express the multiantennal Neu5Ac receptor. Here we also show that mice immunized with inactive typhoid toxins and challenged with wild-type typhoid toxin presented neither the characteristic in vivo tropism nor symptoms. These mice were protected against a lethal-dose toxin challenge, but Ty21a-vaccinated mice were not. Cumulatively, these results reveal remarkable features describing how a bacterial exotoxin induces virulence exclusively in specific cells at the organismal level.

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PMID:
29203881
PMCID:
PMC6045816
DOI:
10.1038/s41564-017-0076-4
[Indexed for MEDLINE]
Free PMC Article

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