The structural basis of Salmonella A2B5 toxin neutralization by antibodies targeting the glycan-receptor binding subunits

• Published in: Cell reports (Cambridge) 2021-09, Vol.36 (10), p.109654-109654, Article 109654
• Main Authors: Nguyen, Tri, Richards, Angelene F., Neupane, Durga P., Feathers, J. Ryan, Yang, Yi-An, Sim, Ji Hyun, Byun, Haewon, Lee, Sohyoung, Ahn, Changhwan, Van Slyke, Greta, Fromme, J. Christopher, Mantis, Nicholas J., Song, Jeongmin
• Format: Article
• Language: English
• Subjects: AB toxin; antibody epitope; asymmeric epitope; bacterial toxin; cryo-EM; glycan receptor; Salmonella Typhi; steric clash; toxin neutralization; typhoid toxin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109654

Many bacterial pathogens secrete A(2)B5 toxins comprising two functionally distinct yet complementary “A” and “B” subunits to benefit the pathogens during infection. The lectin-like pentameric B subunits recognize specific sets of host glycans to deliver the toxin into target host cells. Here, we offer the molecular mechanism by which neutralizing antibodies, which have the potential to bind to all glycan-receptor binding sites and thus completely inhibit toxin binding to host cells, are inhibited from exerting this action. Cryogenic electron microscopy (cryo-EM)-based analyses indicate that the skewed positioning of the toxin A subunit(s) toward one side of the toxin B pentamer inhibited neutralizing antibody binding to the laterally located epitopes, rendering some glycan-receptor binding sites that remained available for the toxin binding and endocytosis process, which is strikingly different from the counterpart antibodies recognizing the far side-located epitopes. These results highlight additional features of the toxin-antibody interactions and offer important insights into anti-toxin strategies. [Display omitted] •Antibodies targeting glycan-receptor binding B subunits can be split into two classes•The two classes are grouped by their epitope locations on the B subunit homopentamer•B homopentamers act similar to heteropentamers due to their skewed A subunit positioning•The two antibody classes exhibit significantly different neutralizing efficacies Nguyen et al. find that toxin-neutralizing antibodies targeting glycan-receptor binding B subunits can be split into two classes based on their epitope locations. They describe how these two classes exhibit significantly different neutralizing efficacies, a feature that appears to be shared among A(2)B5 toxins, and thus they provide insights into anti-toxin strategies.