A Toxin-Antitoxin Module of Salmonella Promotes Virulence in Mice

Matthew A. Mulvey,Stéphane Méresse,Grégory Gimenez,Weidong Zhao,Jean-Pierre Gorvel,Didier Raoult,Miguel A. De la Cruz,Carine Farenc,Christian Cambillau

doi:10.1371/journal.ppat.1003827

Abstract

Toxin-antitoxin (TA) modules are widely prevalent in both bacteria and archaea. Originally described as stabilizing elements of plasmids, TA modules are also widespread on bacterial chromosomes. These modules promote bacterial persistence in response to specific environmental stresses. So far, the possibility that TA modules could be involved in bacterial virulence has been largely neglected, but recent comparative genomic studies have shown that the presence of TA modules is significantly associated with the pathogenicity of bacteria. Using Salmonella as a model, we investigated whether TA modules help bacteria to overcome the stress conditions encountered during colonization, thereby supporting virulence in the host. By bioinformatics analyses, we found that the genome of the pathogenic bacterium Salmonella Typhimurium encodes at least 11 type II TA modules. Several of these are conserved in other pathogenic strains but absent from non-pathogenic species indicating that certain TA modules might play a role in Salmonella pathogenicity. We show that one TA module, hereafter referred to as sehAB, plays a transient role in virulence in perorally inoculated mice. The use of a transcriptional reporter demonstrated that bacteria in which sehAB is strongly activated are predominantly localized in the mesenteric lymph nodes. In addition, sehAB was shown to be important for the survival of Salmonella in these peripheral lymphoid organs. These data indicate that the transient activation of a type II TA module can bring a selective advantage favouring virulence and demonstrate that TA modules are engaged in Salmonella pathogenesis.

Highlights

Prokaryotic genomes contain toxin–antitoxin (TA) loci that induce cell dormancy in response to various stresses [1,2]
In response to unfavourable environmental conditions, the toxin is rapidly freed from the antitoxin and slows down the biological activity of the bacterium
We investigated whether the bacterial pathogen Salmonella possesses similar self-protecting systems and if they are necessary for virulence

Summary

Introduction

Prokaryotic genomes contain toxin–antitoxin (TA) loci that induce cell dormancy in response to various stresses [1,2] This is mediated by the toxin components that target essential cellular processes, such as DNA replication, mRNA stability or protein synthesis (for review see [2]). The recently described type IV and V systems refer to protein-protein modules in which the antitoxin masks the toxin activity either by interfering with binding of the toxin to its target (type IV) [4] or by cleaving the toxin mRNA (type V) [5]. Environmental conditions that favour the degradation of the labile antitoxin raise the level of free toxin and relieve the expression inhibition of the TA locus. This regulation loop maintains a high level of free toxin as long as the conditions supporting the antitoxin degradation are sustained

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Discussion

Conclusion