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Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Teresa Frisan)
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Effekter av bakteriella genotoxiner på immunmodulering, kronisk inflammation och cancerutveckling (Swedish)
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: urn:nbn:se:umu:diva-203905ISBN: 978-91-7855-971-8 (print)ISBN: 978-91-7855-972-5 (print)OAI: oai:DiVA.org:umu-203905DiVA, id: diva2:1730091
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
List of papers
1. Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells
Open this publication in new window or tab >>Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells
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2019 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, no 12, article id e13099Article in journal (Refereed) Published
Abstract [en]

Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
APC, bacteria and cancer, bacterial genotoxin, DNA damage response, DNA repair, organotypic del, tumour-suppressor gene
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-167179 (URN)10.1111/cmi.13099 (DOI)000482652700001 ()31414579 (PubMedID)2-s2.0-85071087704 (Scopus ID)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2023-01-23Bibliographically approved
2. Influence of the microenvironment on modulation of the host response by typhoid toxin
Open this publication in new window or tab >>Influence of the microenvironment on modulation of the host response by typhoid toxin
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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
Keywords
Ataxia-telangiectasia mutated (ATM), bacterial genotoxins, colitis, immune response, immunomodulation, microenviroment, senescence, typhoid toxin
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-182265 (URN)10.1016/j.celrep.2021.108931 (DOI)000637406700002 ()33826883 (PubMedID)2-s2.0-85103781998 (Scopus ID)
Available from: 2021-04-20 Created: 2021-04-20 Last updated: 2024-01-17Bibliographically approved
3. Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa
Open this publication in new window or tab >>Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa
2021 (English)In: STAR Protocols, E-ISSN 2666-1667, Vol. 2, no 4, article id 100833Article in journal (Refereed) Published
Abstract [en]

We recently characterized the association between DNA damage and immunoresponse in vivo in colonic mucosa of mice infected with a Salmonella Typhimurium strain expressing a genotoxin, known as typhoid toxin. In this protocol, we describe how to assess the extent and features of infiltrating macrophages by double immunofluorescence. Total macrophage population was determined using an F4/80 antibody, whereas the specific M2-like population was assessed using a CD206 antibody. For complete details on the use and execution of this protocol, please refer to Martin et al. (2021).

Place, publisher, year, edition, pages
Cell Press, 2021
Keywords
Cell-based assays, In situ hybridization, Microscopy
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-202969 (URN)10.1016/j.xpro.2021.100833 (DOI)2-s2.0-85122830767 (Scopus ID)
Funder
Swedish Cancer Society, 20 0699 PjFSwedish Cancer Society, CAN 2017/315Swedish Research Council, 2018–02521Umeå UniversityThe Kempe Foundations, JCK-1826
Available from: 2023-01-14 Created: 2023-01-14 Last updated: 2023-03-24Bibliographically approved
4. The challenge of establishing immunocompetent human intestinal 3D models
Open this publication in new window or tab >>The challenge of establishing immunocompetent human intestinal 3D models
(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
bacterial genotoxin, bacteria, DNA damage response, organotypic model, immune cells.
National Category
Cell Biology Immunology
Research subject
biology; cell research; Immunology
Identifiers
urn:nbn:se:umu:diva-203903 (URN)
Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-01-24

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