Glycan-mediated molecular interactions in bacterial pathogenesis

Lee, Sohyoung; Inzerillo, Sean; Lee, Gi Young; Bosire, Erick M.; Mahato, Saroj Kumar; Song, Jeongmin

doi:10.1016/j.tim.2021.06.011

Cited by 31 publications

(13 citation statements)

References 107 publications

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“…The competition pattern of T2E7 over each VHH, TyTx1, and TyTx4 was similar to that of TyTx1 ( Fig. 2 ), suggesting that, like TyTx1, T2E7 recognizes amino acids located on/near the glycan receptor-binding pocket 1 essential for its binding to α2-3 and α2-6 sialosides ( 5 , 25 ). Likewise, the competition patterns of T2G9 and TyTx4 were alike ( Fig.…”

Section: Discussionmentioning

confidence: 68%

“…Likewise, the competition patterns of T2G9 and TyTx4 were alike ( Fig. 2 ), suggesting that, like TyTx4, T2G9 recognizes the region on/near the glycan-receptor binding pockets 2 and 3 that are located on the bottom side of PltB, critical for its binding to α2-3 sialosides ( 5 , 25 ). Despite the similarities, we predict that the specific epitopes recognized by T2E7 and T2G9 are not identical to TyTx1 and TyTx4, respectively, as their competition ELISA results are not identical.…”

Section: Discussionmentioning

confidence: 93%

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Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

et al. 2022

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Typhoid toxin is secreted by the typhoid fever-causing bacterial pathogen Salmonella Typhi and has tropism for immune cells and brain endothelial cells. Here, we generated a camelid single domain antibody (VHH) library from typhoid toxoid-immunized alpacas and identified 41 VHHs selected on the glycan-receptor binding PltB and nuclease CdtB. VHHs exhibiting potent in vitro neutralizing activities from each sequence-based family were epitope binned via competition ELISAs, leading to 6 distinct VHHs, two anti-PltB (T2E7 and T2G9) and four anti-CdtB VHHs (T4C4, T4C12, T4E5, and T4E8), whose in vivo neutralizing activities and associated toxin neutralizing mechanisms were investigated. We found that T2E7, T2G9, and T4E5 effectively neutralized typhoid toxin in vivo , as demonstrated by 100% survival of mice administered a lethal-dose of typhoid toxin and with little to no typhoid toxin-mediated upper motor function defect. Cumulatively, these results highlight the potential of the compact antibodies to neutralize typhoid toxin by targeting the glycan-binding and/or nuclease subunits.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 93%

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

et al. 2022

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“…It is worth noting that typhoid toxin orthologs encoded by some clade B nontyphoidal Salmonellae , collectively called Salmonella A 2 B 5 toxins, contain the identical CdtB at the sequence level, while their receptor-binding subunits have variations, which are associated with an altered tropism of toxin variant [ 70 ]. For instance, Javiana toxin from nontyphoidal Salmonella Javiana targets intestinal epithelial cells [ 70 ], which is in line with the coevolution concept for niche-specific adaptations of AB toxins and the cognate bacteria [ 81 ].…”

Section: Delivery Of Bacterial Genotoxinsmentioning

confidence: 89%

Delivery, structure, and function of bacterial genotoxins

Song

2022

Virulence

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Bacterial genotoxins are peptide or protein virulence factors produced by several pathogens, which make single-strand breaks (SSBs) and/or double-strand DNA breaks (DSBs) in the target host cells. If host DNA inflictions are not resolved on time, host cell apoptosis, cell senescence, and/or even bacterial pathogen-related cancer may occur. Two multi-protein AB toxins, cytolethal distending toxin (CDT) produced by over 30 bacterial pathogens and typhoid toxin from Salmonella Typhi, as well as small polyketide-peptides named colibactin that causes the DNA interstrand cross-linking and subsequent DSBs is the most well-characterized bacterial genotoxins. Using these three examples, this review discusses the mechanisms by which these toxins deliver themselves into the nucleus of the target host cells and exert their genotoxic functions at the structural and functional levels.

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“…Although this toxin receptor preference indicates adaptation to non-human Neu5Gc expressing hosts, the lack of Neu5Gc-containing body fluid receptor competitors in humans may confer susceptibility to the gastrointestinal and systemic toxicities of SubAB [131]. In recent years, cellular receptors for other AB 5 toxins have been demonstrated to be host glycan structures [132] (). Salmonella Typhi, the causative agent of typhoid fever in humans, produces the AB 5 Typhoid toxin PltAB, in an A 2 B 5 arrangement.…”

Section: A Sugar Coating Can Kill You: Sialic Acid As Receptors For B...mentioning

confidence: 99%

How bacteria utilize sialic acid during interactions with the host: snip, snatch, dispatch, match and attach

2022

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N -glycolylneuraminic acid (Neu5Gc), and its precursor N-acetylneuraminic acid (Neu5Ac), commonly referred to as sialic acids, are two of the most common glycans found in mammals. Humans carry a mutation in the enzyme that converts Neu5Ac into Neu5Gc, and as such, expression of Neu5Ac can be thought of as a ‘human specific’ trait. Bacteria can utilize sialic acids as a carbon and energy source and have evolved multiple ways to take up sialic acids. In order to generate free sialic acid, many bacteria produce sialidases that cleave sialic acid residues from complex glycan structures. In addition, sialidases allow escape from innate immune mechanisms, and can synergize with other virulence factors such as toxins. Human-adapted pathogens have evolved a preference for Neu5Ac, with many bacterial adhesins, and major classes of toxin, specifically recognizing Neu5Ac containing glycans as receptors. The preference of human-adapted pathogens for Neu5Ac also occurs during biosynthesis of surface structures such as lipo-oligosaccharide (LOS), lipo-polysaccharide (LPS) and polysaccharide capsules, subverting the human host immune system by mimicking the host. This review aims to provide an update on the advances made in understanding the role of sialic acid in bacteria-host interactions made in the last 5–10 years, and put these findings into context by highlighting key historical discoveries. We provide a particular focus on ‘molecular mimicry’ and incorporation of sialic acid onto the bacterial outer-surface, and the role of sialic acid as a receptor for bacterial adhesins and toxins.

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Glycan-mediated molecular interactions in bacterial pathogenesis

Cited by 31 publications

References 107 publications

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Delivery, structure, and function of bacterial genotoxins

How bacteria utilize sialic acid during interactions with the host: snip, snatch, dispatch, match and attach

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