Emerging insights into the biology of typhoid toxin

Abstract

Typhoid toxin is a unique A₂B₅ exotoxin and an important virulence factor for Salmonella Typhi, the cause of typhoid fever. In the decade since its initial discovery, great strides have been made in deciphering the unusual biological program of this toxin, which is fundamentally different from related toxins in many ways. Purified typhoid toxin administered to laboratory animals causes many of the symptoms of typhoid fever, suggesting that typhoid toxin is a central factor in this disease. Further advances in understanding the biology of this toxin will help guide the development of badly needed diagnostics and therapeutic interventions that target this toxin to detect, prevent or treat typhoid fever.

Figure 1. Atomic structures of typhoid toxin

(A) The overall structure of the typhoid holotoxin complex is shown as a ribbon cartoon. CdtB, PltA and PltB are shown in blue, red and green, respectively. The inset shows a detailed view of a critical disulphide bond between PltA Cys214 and CdtB Cys269. (B) Comparison of the sugar binding sites of PltB and SubB bound to Neu5Ac and Neu5Gc, respectively. Critical residues that differ between SubB (Tyr78) and PltB (Val103) are highlighted as sticks. Other interacting amino acids and sugars are shown in lines. PltB and Neu5Ac are shown in green, SubB and Neu5Gc in light brown.

Figure 2. Secretion and export pathways of typhoid toxin

Expression of typhoid toxin is induced shortly after invasion S. Typhi invasion of host cells. Its subunits, CdtB, PltA and PltB, each possess a canonical N-terminal Sec signal peptide indicating that the Sec machinery mediates translocation of the subunits across the cytoplasmic membrane to the periplasm, where holotoxin assembly is thought to occur. Secretion of toxin from the periplasm requires TtsA, an endolysin homolog thought to facilitate toxin secretion through enzymatically modifying the peptidoglycan layer. TtsA lacks a Sec signal sequence and it has been hypothesized that its translocation to the periplasm might be exerted by a yet unidentified holin. Following secretion from the bacterium, the holotoxin is sorted from the lumen of SCV to packaging carrier intermediates, which subsequently export typhoid toxin from the cell. Typhoid toxin packaging requires the specific SCV environment generated through the actions of SPI-2 T3SS-secreted effector proteins, as well as interactions between PltB and specific lumenal Neu5Ac-sialylated glycan packaging receptors. Sec signal peptide (SP), inner membrane (IM), peptidoglycan (PG), outer membrane (OM), Salmonella-containing vacuole (SCV).