Isolation of Highly Persistent Mutants of Salmonella enterica Serovar Typhimurium Reveals a New Toxin-Antitoxin Module

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.

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“…It is very likely that other TA systems exist and will be discovered as illustrated by the recently published study by Slattery et al [35] …”

Section: Discussionmentioning

confidence: 99%

A Toxin-Antitoxin Module of Salmonella Promotes Virulence in Mice

et al. 2013

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“…In addition, a similar lengthening of the lag phase has been observed in the high‐persister mutant shp in Salmonella enterica (Slattery et al . ). The full extent of such fitness trade‐offs and antagonistic pleiotropy, however, has not been examined in detail, and it remains unknown whether also in other species, persistence negatively affects other growth parameters.…”

Section: Introductionmentioning

confidence: 97%

Fitness trade‐offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa

et al. 2015

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Microbial populations often contain a fraction of slow-growing persister cells that withstand antibiotics and other stress factors. Current theoretical models predict that persistence levels should reflect a stable state in which the survival advantage of persisters under adverse conditions is balanced with the direct growth cost impaired under favourable growth conditions, caused by the nonreplication of persister cells. Based on this direct growth cost alone, however, it remains challenging to explain the observed low levels of persistence (<<1%) seen in the populations of many species. Here, we present data from the opportunistic human pathogen Pseudomonas aeruginosa that can explain this discrepancy by revealing various previously unknown costs of persistence. In particular, we show that in the absence of antibiotic stress, increased persistence is traded off against a lengthened lag phase as well as a reduced survival ability during stationary phase. We argue that these pleiotropic costs contribute to the very low proportions of persister cells observed among natural P. aeruginosa isolates (3 × 10(-8) -3 × 10(-4)) and that they can explain why strains with higher proportions of persister cells lose out very quickly in competition assays under favourable growth conditions, despite a negligible difference in maximal growth rate. We discuss how incorporating these trade-offs could lead to models that can better explain the evolution of persistence in nature and facilitate the rational design of alternative therapeutic strategies for treating infectious diseases.

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“…Gallinarum and recently also for S . Enteritidis [26]–[29]. In this study, we have therefore constructed a triple SPI1- lon - fliC mutant of S .…”

Section: Introductionmentioning

confidence: 99%

Vaccination of Chickens with SPI1-lon and SPI1-lon-fliC Mutant of Salmonella enterica Serovar Enteritidis

et al. 2013

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The prevalence of Salmonella enterica serovar Enteritidis is gradually decreasing in poultry flocks in the EU, which may result in the demand for a vaccine that allows for the differentiation of vaccinated flocks from those infected by wild-type S. Enteritidis. In this study, we therefore constructed a (Salmonella Pathogenicity Island 1) SPI1-lon mutant with or without fliC encoding for S. Enteritidis flagellin. The combination of SPI1-lon mutations resulted in attenuated but immunogenic mutant suitable for oral vaccination of poultry. In addition, the vaccination of chickens with the SPI1-lon-fliC mutant enabled the serological differentiation of vaccinated and infected chickens. The absence of fliC therefore did not affect the immunogenicity of the vaccine strain and allowed for serological differentiation of the vaccinated chickens. The SPI1-lon-fliC mutant is therefore a suitable marker vaccine strain for oral vaccination of poultry.

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Isolation of Highly Persistent Mutants of Salmonella enterica Serovar Typhimurium Reveals a New Toxin-Antitoxin Module

Cited by 50 publications

References 75 publications

A Toxin-Antitoxin Module of Salmonella Promotes Virulence in Mice

A Toxin-Antitoxin Module of Salmonella Promotes Virulence in Mice

Fitness trade‐offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa

Vaccination of Chickens with SPI1-lon and SPI1-lon-fliC Mutant of Salmonella enterica Serovar Enteritidis

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