Mechanisms of Typhoid Toxin Neutralization by Antibodies Targeting Receptor-Binding and Nuclease Subunits

Nearly all clinical isolates of Salmonella Typhi, the cause of typhoid fever, are antibiotic-resistant. All S. Typhi isolates secrete an A2B5 exotoxin called typhoid toxin to benefit the pathogen during infection. Here, we demonstrate that antibiotic-resistant S. Typhi secretes typhoid toxin continuously during infection regardless of antibiotic treatment. Typhoid toxin neutralizing antibodies (nAbs) generated in this study target receptor-binding PltB or nuclease CdtB. All nAbs neutralize typhoid toxin in vitro and in vivo, as demonstrated by using typhoid toxin secreted by antibiotic-resistant S. Typhi during human cell infection and lethal-dose typhoid toxin challenge to mice. Cryo-EM analyses explain the mechanisms of how two nAbs, TyTx4 and TyTx11, are more productive; TyTx4 binds to all PltB subunits available per holotoxin, while TyTx11 makes CdtB inactive through CdtB catalytic-site conformational change. The identified toxin neutralizing epitopes are conserved across all S. Typhi clinical isolates, offering critical insights into typhoid toxin neutralizing strategies.