title: Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi.
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.
authors.affiliation: 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.
authors.forename: Lingquan
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, PRC.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Chemistry, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.affiliation: 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.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Naito-Matsui
authors.affiliation: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA. Electronic address: jorge.galan@yale.edu.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Galán
authors.affiliation: 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.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D058507:Host Specificity; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000737:chemistry* / Q000378:metabolism*; D009438:Neuraminic Acids / Q000378:metabolism; D002679:Pan troglodytes; D012485:Salmonella typhi / Q000737:chemistry* / Q000472:pathogenicity; D014435:Typhoid Fever / Q000382:microbiology
chemical_list: D001427:Bacterial Toxins; D008562:Membrane Glycoproteins; D009438:Neuraminic Acids; C032592:N-glycolylneuraminic acid; D019158:N-Acetylneuraminic Acid