Influence of the microenvironment on modulation of the host response by typhoid toxin
Océane C.B. Martin,
Anna Bergonzini,
Maria Lopez Chiloeches,
Eleni Paparouna,
Deborah Butter,
Sofia D.P. Theodorou,
Maria M. Haykal,
Elisa Boutet-Robinet,
Toma Tebaldi,
Andrew Wakeham,
Mikael Rhen,
Vassilis G. Gorgoulis,
Tak Mak,
Ioannis S. Pateras,
Teresa Frisan
Affiliations
Océane C.B. Martin
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
Anna Bergonzini
Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
Maria Lopez Chiloeches
Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
Eleni Paparouna
Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Deborah Butter
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
Sofia D.P. Theodorou
Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Maria M. Haykal
Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, 94800 Villejuif, France
Elisa Boutet-Robinet
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
Toma Tebaldi
Center for Biomedical Data Science, Yale School of Medicine, New Haven, CT, USA
Andrew Wakeham
The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada
Mikael Rhen
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
Vassilis G. Gorgoulis
Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece; Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
Tak Mak
The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada
Ioannis S. Pateras
Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Teresa Frisan
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden; Corresponding author
Summary: 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.
