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The challenge of establishing immunocompetent human intestinal 3D models
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). (Teresa Frisan)
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). (Teresa Frisan)
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Teresa Frisan)
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). (Teresa Frisan)ORCID iD: 0000-0002-1209-0942
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Expression of typhoid toxin in Salmonella Typhimurium causes DNA damage, activating the DNA damage response (DDR), in absence of an inflammatory response in the colonic mucosa of infected mice. The anti-inflammatory effect is tissue specific and is not observed in the liver, suggesting that the local immune microenvironment modulates the DDR outcome.

To assess the role of the immune cells in the DDR outcome induced by the genotoxigenic Salmonella, we have initiated the development of an immunocompetent 3D colonic mucosal model based on a collagen matrix containing colonic fibroblasts and different subtypes of immune cells, overlayed with colonic epithelial cells.

Embedding of peripheral blood mononuclear cells in the collagen matrix did not influenced either the tissue integrity or the activation of the DDR, observed exclusively upon infection with the genotoxigenic strain. However, embedding of T cells, monocytes, or non-polarized macrophages altered the pattern of the DDR and the toxin specific effect was lost. Presence of macrophages was further associated with alteration of the epithelial layer integrity. This effect was infection-dependent, but not toxin specific.

Our data demonstrated that addition of immune cells to a 3D mucosal model altered the DDR induced by a genotoxigenic bacterium, highlighting the need to develop and optimize immunocompetent in vitro models.

Keywords [en]
bacterial genotoxin, bacteria, DNA damage response, organotypic model, immune cells.
National Category
Cell Biology Immunology
Research subject
biology; cell research; Immunology
Identifiers
URN: urn:nbn:se:umu:diva-203903OAI: oai:DiVA.org:umu-203903DiVA, id: diva2:1730085
Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-01-24
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)
Opponent
Supervisors
Available from: 2023-02-03 Created: 2023-01-23 Last updated: 2023-01-25Bibliographically approved

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Bergonzini, AnnaAvila-Cariño, JavierLopez Chiloeches, MariaFrisan, Teresa

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