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

Lisa Del Bel Belluz,Syed Fazle Rouf,Ioannis S Pateras,Teresa Frisan,Clelia Peano,Toma Tebaldi,Boris Mihaljevic,Mikael Rhen,Clarissa Consolandi,Vassilis G Gorgoulis,Claudia Nastasi,Marco Candela,Thorbjørn Krejsgaard,Laura Levi,Riccardo Guidi,Silvia Turroni,Marie Wrande,Gabriella Viero,Andreas J Baumler

doi:10.1371/journal.ppat.1005528

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.

Highlights

Genotoxins have been recently identified as a novel family of microbial effectors in pathogenic and commensal bacteria [1]
Three types of bacterial genotoxins have been identified: the cytolethal distending toxin (CDTs) family, the typhoid toxin and the peptide-polyketide colibactin, all produced by Gram-negative bacteria
The presence of genetic mobile elements upstream and downstream of the genes encoding for some CDT members suggests horizontal transfer, and indicates that these effectors may play a key function in bacterial infection/colonization

Summary

Introduction

Genotoxins have been recently identified as a novel family of microbial effectors in pathogenic and commensal bacteria [1]. Two are protein toxins: the cytolethal distending toxin (CDT) family, produced by Gramnegative extracellular pathogens, such as Escherichia coli, Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter sp. (reviewed in [2]), and the typhoid toxin produced by the facultative intracellular pathogen Salmonella enterica serovar Typhi CDTs are AB2 toxins [4] and the typhoid toxin is an A2B5 toxin [5], where “A” stands for active subunit and “B” for binding moiety. The additional active subunit in the typhoid toxin is homologous to the A subunit of the pertussis toxin, and possesses an ADP-ribosyl transferase activity, for which the cellular targets have not been yet identified [5]. Possibly internalization, of the DNase-like subunit of CDTs and the typhoid toxin are mediated by the “B” subunits CdtA/CdtC and PltB, respectively [4,5]

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