OmpW-mediated sensing of MUC2 GalNAc contributes to the ileal tropism of Salmonella Typhi [STy]

We show that STy exploits MUC2-derived monosaccharides, such as GalNAc, to upregulate invasion and target the ileum—opposite to the response of closely related S. Typhimurium (STm), whose invasion is inhibited by MUC2. Three STy-specific extracellular residues of the outer-membrane protein OmpW (K141/T142/Q193) engage GalNAc, and a periplasmic relay through the short FepE_STy, RS12510, and TonB transmits this signal to activate the master invasion regulator HilD.

Mice lacking MUC2 or gut microbiota lose STy ileal tropism, which is restored by oral GalNAc-containing monosaccharides. An OmpW triple-mutant STy strain establishes a murine oral STy infection model, identifying STy–MUC2 glycan interactions as one of the earliest steps of typhoid pathogenesis and a potential target for prevention.