Host Adaptations of the  &lt;i&gt;Salmonella&lt;/i&gt; Typhi Typhoid Toxin and Its Orthologue from a Nontyphoidal  &lt;i&gt;Salmonella&lt;/i&gt;

Lee, Sohyoung; Yang, Yi-An; Milano, Shawn K.; Nguyen, Tri; Sim, Ji Hyun; Thompson, Andrew J.; Hillpot, E.C.; Yoo, Gyeongshik; Paulson, James C.; Song, Jeongmin

doi:10.2139/ssrn.3413892

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“…This multivalent interaction results in high-affinity bindings as indicated in the glycan microarray results allowing for comparisons of their binding affinities [11]. Epithelial cells of the intestine and the gallbladder also predominantly express multiantennary N-linked glycans [20]. In N-linked glycans, the terminal Neu5Ac can be linked to the underlying Gal-GlcNAc via either α2-3 or α2-6 [21].…”

Section: Host Cells Relevant To Typhoid Toxin-mediated Clinical Signsmentioning

confidence: 99%

“…We previously revealed the three glycan-binding sites (BS) per PltB monomer and demonstrated the flexible use of these three binding sites in accommodating glycan receptor moieties that are structurally different [20]. For instance, Neu5Acα2-3Galβ1-4GlcNAc (α2-3 sialosides) can use all three binding sites of PltBs, BS1-3, while α2-6 sialosides use only one binding site BS1 located at the lateral side of PltBs.…”

Section: Structure Comparison Analysis Of Pltb Subunits Bound To Unmomentioning

confidence: 99%

“…BS2 and 3 are located next to each other at the bottom side of PltB homopentamer ( Fig 4A). Key residues include Ser35 and Lys59 for the BS1, Trp108, Thr109, and Phe113 for the BS2, and Asp28 and Asp29 for the BS3 [20]. To gain insight into the underlying mechanism behind the binding affinity difference between 9-Oacetylated and unmodified glycan receptor moieties, we solved co-crystal structure of PltB homopentamers bound to Neu5,9Ac 2 α2-3Galβ1-4GlcNAc and Neu5,9Ac 2 α2-6Galβ1-4GlcNAc, respectively (Figs 4 and 5, and Table 1).…”

Section: Structure Comparison Analysis Of Pltb Subunits Bound To Unmomentioning

confidence: 99%

“…Typhoid toxin appears to have adapted to glycans predominantly expressed in humans since typhoid toxin does not bind to the otherwise identical glycans terminated by N-glycolylneuraminic acid (Neu5Gc) that many mammals including Chimpanzees express as a major form of sialic acids [19]. Typhoid toxin has tropism to cells expressing multiantennary N-linked glycan receptor moieties terminated in the trisaccharide motif sequence, which include immune cells, brain endothelial cells of arterioles, intestinal and gallbladder epithelial cells [11,20]. The pentameric configuration of the receptor-binding PltB subunit per toxin and the three glycan binding pockets per PltB monomer play an essential role for multivalent interactions between the toxin PltB and glycan receptor moieties [11,20].…”

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confidence: 99%

“…Typhoid toxin has tropism to cells expressing multiantennary N-linked glycan receptor moieties terminated in the trisaccharide motif sequence, which include immune cells, brain endothelial cells of arterioles, intestinal and gallbladder epithelial cells [11,20]. The pentameric configuration of the receptor-binding PltB subunit per toxin and the three glycan binding pockets per PltB monomer play an essential role for multivalent interactions between the toxin PltB and glycan receptor moieties [11,20].…”

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The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

et al. 2020

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Typhoid toxin is an A 2 B 5 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.The Gram-negative rod-shaped bacteria Salmonella enterica serovar Typhi (S. enterica serovar Typhi or S. Typhi) is the cause of the life-threatening disease typhoid fever. Many millions of people including children under the age of five are affected by this infectious disease. Molecular mechanisms underlying typhoid disease progression and the establishment of chronic infection important for the transmission of this human-adapted pathogen are incompletely understood, but typhoid toxin, one of the virulence factors of S. Typhi, is suggested to contribute to these processes. Typhoid toxin consists of three functionally distinct subunits: two enzymatic 'A' subunits important for intoxicating host cells after the delivery into host cells and one homopentamer of receptor-binding 'B' subunit important for the delivery of the toxin into host cells. Typhoid toxin 'B' subunit recognizes specific three-sugar structures decorating the host cell surface, whose terminal sugar called N-acetylneuraminic acid (Neu5Ac) can be present in unmodified or modified forms. The modified Neu5Ac possesses additional chemical groups, with 9-O-acetylation being the most frequently found modification in humans. This study analyzes glycan expression profiles of primary tissues and cells assoc...

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Section: Host Cells Relevant To Typhoid Toxin-mediated Clinical Signsmentioning

confidence: 99%

Section: Structure Comparison Analysis Of Pltb Subunits Bound To Unmomentioning

confidence: 99%

Section: Structure Comparison Analysis Of Pltb Subunits Bound To Unmomentioning

confidence: 99%

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confidence: 99%

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The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

et al. 2020

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Host Adaptations of the <i>Salmonella</i> Typhi Typhoid Toxin and Its Orthologue from a Nontyphoidal <i>Salmonella</i>

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The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication

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