文章基本信息

标题：Mechanisms of typhoid toxin neutralization by antibodies targeting glycan receptor binding and nuclease subunits
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作者：Changhwan Ahn ; Yi-An Yang ; Durga P. Neupane 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：5
页码：1-21
DOI：10.1016/j.isci.2021.102454
语种：English
出版社：Elsevier
摘要：SummaryNearly all clinical isolates ofSalmonellaTyphi, the cause of typhoid fever, are antibiotic resistant. AllS.Typhi isolates secrete an A2B5exotoxin called typhoid toxin to benefit the pathogen during infection. Here, we demonstrate that antibiotic-resistantS.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 toxinin vitroandin vivo, as demonstrated by using typhoid toxin secreted by antibiotic-resistantS.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 allS.Typhi clinical isolates, offering critical insights into typhoid toxin-neutralizing strategies.Graphical abstractDisplay OmittedHighlights•Antibiotic-resistantS.Typhi secretes typhoid toxin despite antibiotic treatment•MAb targeting the receptor-binding or nuclease subunits neutralizes typhoid toxin•TyTx11 makes nuclease CdtB inactive by causing catalytic-site conformational change•Toxin-neutralizing epitopes identified are conserved acrossS.Typhi clinical isolates