The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection

• Published in: PLoS pathogens Vol. 12; no. 4; p. e1005528
• Main Authors: Del Bel Belluz, Lisa, Guidi, Riccardo, Pateras, Ioannis S, Levi, Laura, Mihaljevic, Boris, Rouf, Syed Fazle, Wrande, Marie, Candela, Marco, Turroni, Silvia, Nastasi, Claudia, Consolandi, Clarissa, Peano, Clelia, Tebaldi, Toma, Viero, Gabriella, Gorgoulis, Vassilis G, Krejsgaard, Thorbjørn, Rhen, Mikael, Frisan, Teresa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2016; Public Library of Science (PLoS)
• Subjects: Animals; Asymptomatic Infections; Bacteria; Bacterial infections; Biology and Life Sciences; Cancer; Cell cycle; Colon; Communicable Diseases - microbiology; Confidence intervals; Councils; Deoxyribonucleic acid; DNA; DNA damage; Funding; Genetic aspects; Gram-negative bacteria; Health aspects; Infections; Intestines - microbiology; Kinases; Macrophages - microbiology; Medicin och hälsovetenskap; Medicine and Health Sciences; Mice; Microbial toxins; Mutagens - toxicity; Patient outcomes; Phylogenetics; Principal components analysis; Research and Analysis Methods; Salmonella; Salmonella typhimurium - pathogenicity; Senescence; Toxins; Typhoid fever; Typhoid Fever - microbiology; Virulence
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005528

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.