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Influence of the microenvironment on modulation of the host response by typhoid toxin
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 1, article id 108931Article in journal (Refereed) Published
Abstract [en]

Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

Place, publisher, year, edition, pages
Cell Press , 2021. Vol. 35, no 1, article id 108931
Keywords [en]
Ataxia-telangiectasia mutated (ATM), bacterial genotoxins, colitis, immune response, immunomodulation, microenviroment, senescence, typhoid toxin
National Category
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-182265DOI: 10.1016/j.celrep.2021.108931ISI: 000637406700002PubMedID: 33826883Scopus ID: 2-s2.0-85103781998OAI: oai:DiVA.org:umu-182265DiVA, id: diva2:1545945
Available from: 2021-04-20 Created: 2021-04-20 Last updated: 2024-01-17Bibliographically approved
In thesis
1. Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
Open this publication in new window or tab >>Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Effekter av bakteriella genotoxiner på immunmodulering, kronisk inflammation och cancerutveckling
Abstract [en]

The intestinal microbiome of Inflammatory Bowel Disease and colorectal cancer patients is enriched in genotoxin-producing bacteria, which cause DNA damage in the host cells.

Genotoxins have recently been identified as a novel family of effectors produced by pathogenic and commensal bacteria. At present, only three types of bacterial genotoxins have been identified: colibactin, produced by some Escherichia coli strains; cytolethal distending toxins, produced by several Gram-negative pathogens; and the typhoid toxin, produced by Salmonella enterica serovar Typhi.

Exposure to high toxin doses activates the classical DNA damage response, which consequently blocks proliferation and eventually induces death in mammalian cells. However, exposure to low toxin doses has shown to promote classical signs of carcinogenesis in vitro, such as cell survival and acquisition of genomic instability. Despite an extensive characterization of their mode of action in vitro, we have a poor understanding of genotoxins´ role in chronic infection and, considering the genotoxic potential, of their carcinogenic capacity. To investigate further the role played by the genotoxins, we focused specifically on Salmonella Typhi, since it is the only genotoxin-producing bacterium that induces a chronic infection associated with increased risk of tumor development in humans. 

The results presented in this thesis show that these unusual bacterial effectors are not classical toxins, but rather act as immunomodulators, highlighting a complex and tissue-specific crosstalk between two highly conserved stress responses: the immune response and the DNA damage response. 

Our data indicate that the impact of genotoxin-producing bacteria on the modulation of the host mucosal response is still poorly characterized and suggest that the host-microbe interaction and the tissue microenvironment are the key players in determining the outcome of the infection and the toxin carcinogenic potential. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 93
National Category
Immunology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-203905 (URN)978-91-7855-971-8 (ISBN)978-91-7855-972-5 (ISBN)
Public defence
2023-02-24, Major Groove, Department of Molecular Biology, University hospital area, building 6L., Umeå, 09:00 (English)
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Supervisors
Available from: 2023-02-03 Created: 2023-01-23 Last updated: 2023-01-25Bibliographically approved

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Bergonzini, AnnaLopez Chiloeches, Maria

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