6tyo

Publication Abstract from PubMed

Typhoid toxin is an A2B5 toxin secreted from Salmonella Typhi-infected cells during human infection and is suggested to contribute to typhoid disease progression and the establishment of chronic infection. To deliver the enzymatic 'A' subunits of the toxin to the site of action in host cells, the receptor-binding 'B' subunit PltB binds to the trisaccharide glycan receptor moieties terminated in N-acetylneuraminic acid (Neu5Ac) that is alpha2-3 or alpha2-6 linked to the underlying disaccharide, galactose (Gal) and N-acetylglucosamine (GlcNAc). Neu5Ac is present in both unmodified and modified forms, with 9-O-acetylated Neu5Ac being the most common modification in humans. Here we show that host cells associated with typhoid toxin-mediated clinical signs express both unmodified and 9-O-acetylated glycan receptor moieties. We found that PltB binds to 9-O-acetylated alpha2-3 glycan receptor moieties with a markedly increased affinity, while the binding affinity to 9-O-acetylated alpha2-6 glycans is only slightly higher, as compared to the affinities of PltB to the unmodified counterparts, respectively. We also present X-ray co-crystal structures of PltB bound to related glycan moieties, which supports the different effects of 9-O-acetylated alpha2-3 and alpha2-6 glycan receptor moieties on the toxin binding. Lastly, we demonstrate that the cells exclusively expressing unmodified glycan receptor moieties are less susceptible to typhoid toxin than the cells expressing 9-O-acetylated counterparts, although typhoid toxin intoxicates both cells. These results reveal a fine-tuning mechanism of a bacterial toxin that exploits specific chemical modifications of its glycan receptor moieties for virulence and provide useful insights into the development of therapeutics against typhoid fever.

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication.,Nguyen T, Lee S, Yang YA, Ahn C, Sim JH, Kei TG, Barnard KN, Yu H, Millano SK, Chen X, Parrish CR, Song J PLoS Pathog. 2020 Feb 21;16(2):e1008336. doi: 10.1371/journal.ppat.1008336. PMID:32084237^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.