Mechanisms of typhoid toxin neutralization by antibodies targeting glycan receptor binding and nuclease subunits
Changhwan Ahn,
Yi-An Yang,
Durga P. Neupane,
Tri Nguyen,
Angelene F. Richards,
Ji Hyun Sim,
Nicholas J. Mantis,
Jeongmin Song
Affiliations
Changhwan Ahn
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Yi-An Yang
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Durga P. Neupane
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Tri Nguyen
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Angelene F. Richards
Department of Biomedical Sciences, University at Albany, Albany, NY 12222, USA
Ji Hyun Sim
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Nicholas J. Mantis
Department of Biomedical Sciences, University at Albany, Albany, NY 12222, USA; Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA
Jeongmin Song
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA; Corresponding author
Summary: 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. We characterize typhoid toxin antibodies targeting glycan-receptor-binding PltB or nuclease CdtB, which 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. TyTx11 generated in this study neutralizes typhoid toxin effectively, comparable to TyTx4 that binds to all PltB subunits available per holotoxin. Cryoelectron microscopy explains that the binding of TyTx11 to CdtB makes this subunit 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.
