Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi

Lingquan Deng; Jeongmin Song; Xiang Gao; Jiawei Wang; Hai Yu; Xi Chen; Nissi Varki; Yuko Naito-Matsui; Jorge E Galán; Ajit Varki

doi:10.1016/j.cell.2014.10.057

Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi

Cell. 2014 Dec 4;159(6):1290-9. doi: 10.1016/j.cell.2014.10.057.

Authors

Lingquan Deng¹, Jeongmin Song², Xiang Gao², Jiawei Wang³, Hai Yu⁴, Xi Chen⁴, Nissi Varki⁵, Yuko Naito-Matsui¹, Jorge E Galán⁶, Ajit Varki⁷

Affiliations

¹ Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
³ School of Life Sciences, Tsinghua University, Beijing 100084, PRC.
⁴ Department of Chemistry, University of California, Davis, Davis, CA 95616, USA.
⁵ Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA. Electronic address: jorge.galan@yale.edu.
⁷ Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: a1varki@ucsd.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Bacterial Toxins / chemistry*
Bacterial Toxins / genetics
Bacterial Toxins / metabolism*
Cell Line
Cells, Cultured
Crystallography, X-Ray
Host Specificity
Humans
Jurkat Cells
Membrane Glycoproteins / chemistry*
Mice
Mice, Inbred C57BL
Models, Molecular
N-Acetylneuraminic Acid / chemistry*
N-Acetylneuraminic Acid / metabolism*
Neuraminic Acids / metabolism
Pan troglodytes
Salmonella typhi / chemistry*
Salmonella typhi / pathogenicity
Typhoid Fever / microbiology

Substances

Bacterial Toxins
Membrane Glycoproteins
Neuraminic Acids
N-glycolylneuraminic acid
N-Acetylneuraminic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding