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.