Srour, S. orcid.org/0000-0002-6292-428X, Brown, F.K. orcid.org/0000-0003-1642-3262, Sheffield, J.W. et al. (7 more authors) (2025) Typhoid toxin of Salmonella Typhi elicits host antimicrobial response during acute typhoid fever. EMBO Molecular Medicine. ISSN: 1757-4676
Abstract
Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.
Metadata
| Item Type: | Article |
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| Copyright, Publisher and Additional Information: | © The Author(s) 2025. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible. |
| Dates: |
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| Institution: | The University of Sheffield |
| Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
| Date Deposited: | 08 Dec 2025 10:55 |
| Last Modified: | 08 Dec 2025 10:57 |
| Status: | Published online |
| Publisher: | Springer Science and Business Media LLC |
| Refereed: | Yes |
| Identification Number: | 10.1038/s44321-025-00347-8 |
| Related URLs: | |
| Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:235137 |

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