Salmonella Typhoid Toxin PltB Subunit and Its Non-typhoidal Salmonella Ortholog Confer Differential Host Adaptation and Virulence

• Published in: Cell host & microbe 2020-06, Vol.27 (6), p.937-949.e6
• Main Authors: Lee, Sohyoung, Yang, Yi-An, Milano, Shawn K., Nguyen, Tri, Ahn, Changhwan, Sim, Ji Hyun, Thompson, Andrew J., Hillpot, Eric C., Yoo, Gyeongshik, Paulson, James C., Song, Jeongmin
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antitoxins - immunology; bacterial AB toxins; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; Bacterial Proteins - toxicity; Bacterial Toxins - genetics; Bacterial Toxins - immunology; Bacterial Toxins - metabolism; Bacterial Toxins - toxicity; Cross Reactions - immunology; cross-reactive protection or immunity; Endotoxins - genetics; Endotoxins - immunology; Endotoxins - metabolism; Endotoxins - toxicity; Female; glycan expression; glycans; HEK293 Cells; Host Adaptation - drug effects; Host Adaptation - physiology; host adaptations; Humans; Male; Mice, Knockout; Polysaccharides - biosynthesis; receptor-binding; Salmonella; Salmonella typhi - immunology; Salmonella typhi - metabolism; Salmonella typhi - pathogenicity; structure of protein toxins; typhoid fever; Typhoid Fever - microbiology; Typhoid Fever - prevention & control; typhoid toxin; Typhoid-Paratyphoid Vaccines - immunology; Virulence
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.04.005

Typhoidal and non-typhoidal Salmonelleae (NTS) cause typhoid fever and gastroenteritis, respectively, in humans. Salmonella typhoid toxin contributes to typhoid disease progression and chronic infection, but little is known about the role of its NTS ortholog. We found that typhoid toxin and its NTS ortholog induce different clinical presentations. The PltB subunit of each toxin exhibits different glycan-binding preferences that correlate with glycan expression profiles of host cells targeted by each bacterium at the primary infection or intoxication sites. Through co-crystal structures of PltB subunits bound to specific glycan receptor moieties, we show that they induce markedly different glycan-binding preferences and virulence outcomes. Furthermore, immunization with the NTS S. Javiana or its toxin offers cross-reactive protection against lethal-dose typhoid toxin challenge. Cumulatively, these results offer insights into the evolution of host adaptations in Salmonella AB toxins, their cell and tissue tropisms, and the design for improved typhoid vaccines and therapeutics. [Display omitted] •Typhoid toxin and non-typhoid Javiana toxin induce different clinical presentations•Typhoid toxin PltB uses both α2-3 and α2-6 sialosides to enter target cells•Amino acid variations in Javiana PltB render different glycan-binding preferences•Javiana toxin offers cross-reactive protection against typhoid toxin challenge Through structural and functional analyses of the typhoid-fever-causing Salmonella’s typhoid toxin and its ortholog in non-typhoidal, self-limiting gastroenteritis-causing Salmonella, Lee et al. offer insights into the evolution of host adaptations in Salmonella AB toxins, as well as the design for improved typhoid fever vaccines and therapeutics.