Host Adaptation of a Bacterial Toxin from the Human Pathogen Salmonella Typhi

• Published in: Cell 2014-12, Vol.159 (6), p.1290-1299
• Main Authors: Deng, Lingquan, Song, Jeongmin, Gao, Xiang, Wang, Jiawei, Yu, Hai, Chen, Xi, Varki, Nissi, Naito-Matsui, Yuko, Galán, Jorge E., Varki, Ajit
• Format: Article
• Language: English
• Subjects: Animals; bacterial toxins; Bacterial Toxins - chemistry; Bacterial Toxins - genetics; Bacterial Toxins - metabolism; Cell Line; Cells, Cultured; Crystallography, X-Ray; glycoproteins; Host Specificity; Humans; Jurkat Cells; laboratory animals; Membrane Glycoproteins - chemistry; Mice; Mice, Inbred C57BL; Models, Molecular; N-Acetylneuraminic Acid - chemistry; N-Acetylneuraminic Acid - metabolism; Neuraminic Acids - metabolism; Pan troglodytes; pathogens; polysaccharides; Salmonella Typhi; Salmonella typhi - chemistry; Salmonella typhi - pathogenicity; tissues; toxicity; typhoid fever; Typhoid Fever - microbiology; virulence
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.10.057

Salmonella Typhi is an exclusive human pathogen that causes typhoid fever. Typhoid toxin is a S. Typhi virulence factor that can reproduce most of the typhoid fever symptoms in experimental animals. Toxicity depends on toxin binding to terminally sialylated glycans on surface glycoproteins. Human glycans are unusual because of the lack of CMAH, which in other mammals converts N-acetylneuraminic acid (Neu5Ac) to N-glycolylneuraminic acid (Neu5Gc). Here, we report that typhoid toxin binds to and is toxic toward cells expressing glycans terminated in Neu5Ac (expressed by humans) over glycans terminated in Neu5Gc (expressed by other mammals). Mice constitutively expressing CMAH thus displaying Neu5Gc in all tissues are resistant to typhoid toxin. The atomic structure of typhoid toxin bound to Neu5Ac reveals the structural bases for its binding specificity. These findings provide insight into the molecular bases for Salmonella Typhi’s host specificity and may help the development of therapies for typhoid fever. [Display omitted] •Salmonella Typhi is an exclusive human pathogen in whom it causes typhoid fever•Typhoid toxin can reproduce the symptoms of typhoid fever in experimental animals•Typhoid toxin binds glycans present in human cells, but not those in other mammals•The atomic structure of the toxin/receptor complex shows the bases for specificity An enzyme that modifies glycans on surface glycoproteins of cells is missing in humans when compared to other mammals and could explain the binding specificity and toxicity of a toxin produced by Salmonella Typhi, a pathogen that exclusively infects humans and causes typhoid fever.