Abstract
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 α2–3 or α2–6 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 α2–3 glycan receptor moieties with a markedly increased affinity, while the binding affinity to 9-O-acetylated α2–6 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 α2–3 and α2–6 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.
Highlights
This study analyzes glycan expression profiles of primary tissues and cells associated with typhoid clinical signs, the interface between the toxin and glycan receptor moieties through biochemical and structural approaches, and typhoid toxin intoxication profiles of host cells that are genetically engineered to alter the expression of related glycans
Host cells relevant to typhoid toxin-mediated clinical signs express both unmodified and 9-O-acetylated glycan receptor moieties
The effects of modified sialic acids on the typhoid toxin binding and intoxication administered systemically into mice, typhoid toxin displays tropism to immune cells and brain endothelial cells of arterioles [11]. This toxin tropism is primarily due to the abundant expression of multiantennary N-linked glycans terminated in the trisaccharide motif (Neu5Ac-GalGlcNAc) that typhoid toxin recognizes
Summary
Depletion of immune cells as known as leukopenia is a characteristic sign of severe typhoid fever [2,3,4,5,6]. A secreted soluble protein virulence factor known as typhoid toxin appears to contribute to these clinical signs and symptoms during human infection. When administered to laboratory animals, typhoid toxin recapitulates many of the severe acute-phase symptoms of typhoid fever, such as lethargy, malaise, and stupor (the meaning of typhos in Greek), along with leukopenia and neurologic complications [10, 11]. Primary human cells and tissues relevant to typhoid clinical signs and symptoms express the specific glycan receptor moieties for typhoid toxin [11], whether at least some of the glycan receptor moieties are further modified by additional chemical groups has not been revealed
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