Unlike most salmonellae, Salmonella enterica serovar Typhi causes life-threatening systemic infections known as typhoid fever, for which the molecular basis is unknown; here administration of typhoid toxin produced by S. Typhi reproduces many of the acute symptoms of typhoid fever, carbohydrates on cell surface glycoproteins are identified as receptors for typhoid toxin and the toxin’s crystal structure is determined, providing insights into these interactions. The biological basis for the pathogenic properties of Salmonella enterica serovar Typhi (S. Typhi) is largely unknown. S. Typhi causes life-threatening systemic infections known as typhoid fever, whereas most other Salmonella enterica serotypes are either harmless or associated with less-serious gastric infections or food poisoning. This study shows that administration of typhoid toxin, a novel AB toxin composed of two A subunits unique to S. Typhi, reproduces many of the acute symptoms of typhoid fever. The authors go on to identify carbohydrates on cell-surface glycoproteins as receptors for typhoid toxin and determine the toxin's crystal structure, providing insights into these interactions. Theses advances suggest that antitoxin-based therapeutics may be effective in treating typhoid. Salmonella enterica serovar Typhi (S. Typhi) differs from most other salmonellae in that it causes a life-threatening systemic infection known as typhoid fever1. The molecular bases for its unique clinical presentation are unknown2. Here we find that the systemic administration of typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of typhoid fever in an animal model. We identify specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of typhoid toxin, which shows an unprecedented A2B5 organization with two covalently linked A subunits non-covalently associated to a pentameric B subunit. The structure provides insight into the toxin’s receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been co-opted into a single, unique toxin that can induce many of the symptoms characteristic of typhoid fever. These findings may lead to the development of potentially life-saving therapeutics against typhoid fever.

Antiporter Antics: Bacteria that survive in the acidic environment of the stomach have mechanisms to maintain a high intracellular pH. In Escherichia coli , glutamate (Glu) and arginine (Arg) are decarboxylated intracellularly and the reaction products are exchanged with extracellular Glu and Arg. Gao et al. (p. 1565 , published online 28 May) now report a crystal structure of AdiC, an arginine:agmatine antiporter from E. coli . AdiC exhibits the same fold as that of the Na ⁺ -coupled symporters, including LeuT. It contains 12 transmembrane segments, forms a homodimer, and exists in an outward-facing, open conformation in the crystals. The structure, together with biochemical data, suggests how the antiporter senses the pH and responds to transport the reaction product agmatine out of the cell and Arg into the cell.