OmpW-mediated sensing of MUC2 GalNAc contributes to the ileal tropism of Salmonella Typhi.

Salmonella Typhi (STy), the causative agent of typhoid fever, preferentially infects the ileum, but the basis for this preference has remained unknown. We show that STy exploits MUC2-derived monosaccharides, such as N-acetylgalactosamine (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 an early step of typhoid pathogenesis and a potential target for prevention.