The Structural Basis of Salmonella A 2 B 5 Neutralization by Antibodies Targeting the Glycan-Receptor Binding Subunits

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 with the potential to bind to all the glycan receptor-binding sites and thus completely inhibit the toxin binding to host cells were unable to do so. 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 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 new features in the toxin-antibody interactions and offer important insights into anti-toxin strategies.