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TitleMechanisms of typhoid toxin neutralization by antibodies targeting glycan receptor binding and nuclease subunits.
Journal, issue, pagesiScience, Vol. 24, Issue 5, Page 102454, Year 2021
Publish dateMay 21, 2021
AuthorsChanghwan Ahn / Yi-An Yang / Durga P Neupane / Tri Nguyen / Angelene F Richards / Ji Hyun Sim / Nicholas J Mantis / Jeongmin Song /
PubMed AbstractNearly all clinical isolates of Typhi, the cause of typhoid fever, are antibiotic resistant. All Typhi isolates secrete an AB exotoxin called typhoid toxin to benefit the pathogen during infection. ...Nearly all clinical isolates of Typhi, the cause of typhoid fever, are antibiotic resistant. All Typhi isolates secrete an AB exotoxin called typhoid toxin to benefit the pathogen during infection. Here, we demonstrate that antibiotic-resistant 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 and , as demonstrated by using typhoid toxin secreted by antibiotic-resistant 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 Typhi clinical isolates, offering critical insights into typhoid toxin-neutralizing strategies.
External linksiScience / PubMed:34113815 / PubMed Central
MethodsEM (single particle)
Resolution3.12 Å
Structure data

21429

6vx4

EMDB-21429, PDB-6vx4:
Density-fitted Model Structure of Antibody Variable Domains of TyTx11 in Complex with Typhoid Toxin
Method: EM (single particle) / Resolution: 3.12 Å

Source
  • salmonella enterica subsp. enterica serovar typhi str. ct18 (bacteria)
  • mus musculus (house mouse)
KeywordsTOXIN / Typhoid Toxin / A2B5 / Antibody / Fab

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