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Lopez Chiloeches, Maria
Publications (5 of 5) Show all publications
Lopez Chiloeches, M., Bergonzini, A., Martin, O. C. B., Bergstein, N., Erttmann, S. F., Aung, K. M., . . . Frisan, T. (2023). Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes. Frontiers in Immunology, 14, Article ID 1270449.
Open this publication in new window or tab >>Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1270449Article in journal (Refereed) Published
Abstract [en]

Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.

Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.

Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.

Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
bacterial genotoxin, DNA damage response, inflammasome, inflammation, tissue specificity
National Category
Immunology Microbiology
Identifiers
urn:nbn:se:umu:diva-220315 (URN)10.3389/fimmu.2023.1270449 (DOI)001150445700001 ()38274797 (PubMedID)2-s2.0-85183041210 (Scopus ID)
Funder
Swedish Cancer Society, 20 0699 PjFSwedish Research Council, 2021-00960The Kempe Foundations, SMK-1962The Kempe Foundations, JCK-1826The Kempe Foundations, JCK-3110Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Lopez Chiloeches, M., Bergonzini, A. & Frisan, T. (2021). Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators. Toxins, 13(6), Article ID 426.
Open this publication in new window or tab >>Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators
2021 (English)In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 13, no 6, article id 426Article, review/survey (Refereed) Published
Abstract [en]

The idea that bacterial toxins are not only killers but also execute more sophisticated roles during bacteria-host interactions by acting as negotiators has been highlighted in the past decades. Depending on the toxin, its cellular target and mode of action, the final regulatory outcome can be different. In this review, we have focused on two families of bacterial toxins: genotoxins and pore-forming toxins, which have different modes of action but share the ability to modulate the host's immune responses, independently of their capacity to directly kill immune cells. We have addressed their immuno-suppressive effects with the perspective that these may help bacteria to avoid clearance by the host's immune response and, concomitantly, limit detrimental immunopathology. These are optimal conditions for the establishment of a persistent infection, eventually promoting asymptomatic carriers. This immunomodulatory effect can be achieved with different strategies such as suppression of pro-inflammatory cytokines, re-polarization of the immune response from a pro-inflammatory to a tolerogenic state, and bacterial fitness modulation to favour tissue colonization while preventing bacteraemia. An imbalance in each of those effects can lead to disease due to either uncontrolled bacterial proliferation/invasion, immunopathology, or both.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
bacterial genotoxins, pore-forming toxins, immunoregulation, cytokines, polarization immune response, innate and adaptive immunity
National Category
Immunology in the medical area Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-187370 (URN)10.3390/toxins13060426 (DOI)000665917200001 ()34204481 (PubMedID)2-s2.0-85109964915 (Scopus ID)
Funder
Swedish Cancer Society, 2017/315, 20 0699 PjFSwedish Research Council, 2018-02521The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20- 993, AMP 17-884
Available from: 2021-09-09 Created: 2021-09-09 Last updated: 2023-03-24Bibliographically approved
Lopez Chiloeches, M., Bergonzini, A., Frisan, T. & Martin, O. C. .. (2021). Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa. STAR Protocols, 2(4), Article ID 100833.
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
Martin, O. C. .., Bergonzini, A., Lopez Chiloeches, M., Paparouna, E., Butter, D., Theodorou, S. D. .., . . . Frisan, T. (2021). Influence of the microenvironment on modulation of the host response by typhoid toxin. Cell Reports, 35(1), Article ID 108931.
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
Bergonzini, A., Avila-Cariño, J., Lopez Chiloeches, M. & Frisan, T. 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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