title: The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection.
abstract: Bacterial genotoxins, produced by several Gram-negative bacteria, induce DNA damage in the target cells. While the responses induced in the host cells have been extensively studied in vitro, the role of these effectors during the course of infection remains poorly characterized. To address this issue, we assessed the effects of the Salmonella enterica genotoxin, known as typhoid toxin, in in vivo models of murine infection. Immunocompetent mice were infected with isogenic S. enterica, serovar Typhimurium (S. Typhimurium) strains, encoding either a functional or an inactive typhoid toxin. The presence of the genotoxic subunit was detected 10 days post-infection in the liver of infected mice. Unexpectedly, its expression promoted the survival of the host, and was associated with a significant reduction of severe enteritis in the early phases of infection. Immunohistochemical and transcriptomic analysis confirmed the toxin-mediated suppression of the intestinal inflammatory response. The presence of a functional typhoid toxin further induced an increased frequency of asymptomatic carriers. Our data indicate that the typhoid toxin DNA damaging activity increases host survival and favours long-term colonization, highlighting a complex cross-talk between infection, DNA damage response and host immune response. These findings may contribute to understand why such effectors have been evolutionary conserved and horizontally transferred among Gram-negative bacteria.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Del Bel Belluz
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Guidi
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Pateras
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Levi
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Boris
authors.initials: B
authors.lastname: Mihaljevic
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Syed Fazle
authors.initials: SF
authors.lastname: Rouf
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Wrande
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Candela
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Turroni
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nastasi
authors.affiliation: Institute of Biomedical Technologies, Italian National Research Council, Segrate, Milan, Italy.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Consolandi
authors.affiliation: Institute of Biomedical Technologies, Italian National Research Council, Segrate, Milan, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Peano
authors.affiliation: Centre for Integrative Biology University of Trento, Trento, Italy.
authors.forename: Toma
authors.initials: T
authors.lastname: Tebaldi
authors.affiliation: Institute of Biophysics of CNR, Trento, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Viero
authors.affiliation: Department of Histology and Embryology, School of Medicine, 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, United Kingdom.|Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Krejsgaard
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Rhen
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Frisan
mesh_terms: D000818:Animals; D058345:Asymptomatic Infections; D003141:Communicable Diseases / Q000382:microbiology*; D007422:Intestines / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D014435:Typhoid Fever / Q000382:microbiology*; D014774:Virulence
chemical_list: D009153:Mutagens