Typhoid toxin sorting and exocytic transport from Salmonella Typhi-infected cells

Typhoid toxin is an essential virulence factor for Salmonella Typhi, the cause of typhoid fever in humans. This toxin has an unusual biology in that it is produced by Salmonella Typhi only when located within host cells. Once synthesized, the toxin is secreted to the lumen of the Salmonella-containing vacuole from where it is transported to the extracellular space by vesicle carrier intermediates. Here, we report the identification of the typhoid toxin sorting receptor and components of the cellular machinery that packages the toxin into vesicle carriers, and exports it to the extracellular space. We found that the cation-independent mannose-6-phosphate receptor serves as typhoid toxin sorting receptor and that the coat protein COPII and the GTPase Sar1 mediate its packaging into vesicle carriers. Formation of the typhoid toxin carriers requires the specific environment of the Salmonella Typhi-containing vacuole, which is determined by the activities of specific effectors of its type III protein secretion systems. We also found that Rab11B and its interacting protein Rip11 control the intracellular transport of the typhoid toxin carriers, and the SNARE proteins VAMP7, SNAP23, and Syntaxin 4 their fusion to the plasma membrane. Typhoid toxin's cooption of specific cellular machinery for its transport to the extracellular space illustrates the remarkable adaptation of an exotoxin to exert its function in the context of an intracellular pathogen.

Automated summary

Typhoid toxin, produced by Salmonella Typhi within host cells, is transported to the extracellular space through vesicle carriers. The sorting receptor and cellular machinery involved in the packaging and transport of typhoid toxin have been identified. Specific effectors of type III protein secretion systems determine the formation of typhoid toxin carriers in the Salmonella Typhi-containing vacuole. Rab11B, Rip11, VAMP7, SNAP23, and Syntaxin 4 play important roles in the intracellular transport and fusion of the toxin carriers.