Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin

Abstract

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.