Date Published: December 19, 2013
Publisher: Public Library of Science
Author(s): Miguel A. De la Cruz, Weidong Zhao, Carine Farenc, Grégory Gimenez, Didier Raoult, Christian Cambillau, Jean-Pierre Gorvel, Stéphane Méresse, Matthew A. Mulvey.
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.
Prokaryotic genomes contain toxin–antitoxin (TA) loci that induce cell dormancy in response to various stresses , . This is mediated by the toxin components that target essential cellular processes, such as DNA replication, mRNA stability or protein synthesis (for review see ). Five types of TA systems have been described. In type I and III, the antitoxin is a RNA molecule that either regulates toxin gene expression (type I) or forms a complex with the toxin protein and inhibits its activity (type III) . 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)  or by cleaving specifically the toxin mRNA (type V) . In type II modules, toxin and antitoxin are proteins that are co-transcribed from an operon. By binding its cognate toxin, the antitoxin blocks the toxin activity. Very often, the antitoxin binds to a palindromic stretch within the promoter region and represses the transcription of the operon. Environmental conditions that favour the degradation of the labile antitoxin raise the level of free toxin and also 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.
Type II TA modules are inhibitors of translation that induce bacterial dormancy. Being in a dormant state helps bacteria to survive harmful environments. For example, type II TA modules favour resistance to antibiotics . This study presents evidence that virulent strains of Salmonella possess multiple TA systems and shows that one of these is beneficial in the early phase of infection by the natural route.