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

Yi An Yang, Sohyoung Lee, Jun Zhao, Andrew J. Thompson, Ryan McBride, Buyankhishig Tsogtbaatar, James C. Paulson, Ruth Nussinov, Lingquan Deng, Jeongmin Song*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalNature Microbiology
Volume3
Issue number2
DOIs
StatePublished - 1 Feb 2018

Funding

FundersFunder number
USDA/NIFA1010701
National Institutes of Health
National Cancer InstituteHHSN261200800001E, ZIABC010440
National Institute on Deafness and Other Communication DisordersR01 AI114730
Cornell University

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