Salmonella enterica serovar typhi limits the potency of typhoid toxin and ADP ‐ribosylating toxin AB to establish a persistent infection

Chronic infection is important for the transmission of Salmonella enterica serovar Typhi (S. Typhi), an obligate human pathogen responsible for typhoid fever. The immunomodulatory action of typhoid toxin helps establish an initial stealth invasion of the intestinal tract that can lead to systemic spread, colonization of the gallbladder, and persistent shedding. Typhoid toxin contains a cell-binding pentamer and two catalytic subunits: cytolethal distending toxin B (CdtB, a DNase) and pertussis-like toxin A (PltA, an ADP-ribosyltransferase). It undergoes endocytosis and transport to the endoplasmic reticulum (ER) where toxin disassembly occurs. This allows the catalytic subunits to exit the ER for interaction with their nuclear or cytosolic targets. However, all known cellular and physiological effects of typhoid toxin are attributed to CdtB. These effects reduce the severity of intestinal inflammation, promoting host survival and long-term infections. PltA has in vitro enzymatic activity but does not affect cells challenged with typhoid toxin. It is thought that the cytosolic action of PltA will be identified in future work. We instead propose that PltA never reaches the cytosol: it is retained in the ER to limit toxin potency, thereby allowing the anti-inflammatory effects of CdtB to promote intestinal colonization. The absence of Salmonella ADP-ribosylating toxin AB (ArtAB) from all strains of S. Typhi may serve a similar purpose. We accordingly propose a model of balanced pathogenicity in which the lack of toxin ADP-ribosyltransferase activity is essential for S. Typhi pathogenesis.