Toxin-Antitoxin Systems Are Important for Niche-Specific Colonization and Stress Resistance of Uropathogenic Escherichia coli

Guy Tran Van Nhieu,J Paul Norton,Matthew A Mulvey

doi:10.1371/journal.ppat.1002954

Guy Tran Van Nhieu, J Paul Norton + Show 1 more

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https://doi.org/10.1371/journal.ppat.1002954

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Journal: PLoS Pathogens	Publication Date: Oct 4, 2012
Citations: 221	License type: CC BY 4.0

Affiliation: University of Utah

Abstract

Toxin-antitoxin (TA) systems are prevalent in many bacterial genomes and have been implicated in biofilm and persister cell formation, but the contribution of individual chromosomally encoded TA systems during bacterial pathogenesis is not well understood. Of the known TA systems encoded by Escherichia coli, only a subset is associated with strains of extraintestinal pathogenic E. coli (ExPEC). These pathogens colonize diverse niches and are a major cause of sepsis, meningitis, and urinary tract infections. Using a murine infection model, we show that two TA systems (YefM-YoeB and YbaJ-Hha) independently promote colonization of the bladder by the reference uropathogenic ExPEC isolate CFT073, while a third TA system comprised of the toxin PasT and the antitoxin PasI is critical to ExPEC survival within the kidneys. The PasTI TA system also enhances ExPEC persister cell formation in the presence of antibiotics and markedly increases pathogen resistance to nutrient limitation as well as oxidative and nitrosative stresses. On its own, low-level expression of PasT protects ExPEC from these stresses, whereas overexpression of PasT is toxic and causes bacterial stasis. PasT-induced stasis can be rescued by overexpression of PasI, indicating that PasTI is a bona fide TA system. By mutagenesis, we find that the stress resistance and toxic effects of PasT can be uncoupled and mapped to distinct domains. Toxicity was specifically linked to sequences within the N-terminus of PasT, a region that also promotes the development of persister cells. These results indicate discrete, multipurpose functions for a TA-associated toxin and demonstrate that individual TA systems can provide bacteria with pronounced fitness advantages dependent on toxin expression levels and the specific environmental niche occupied.

Highlights

Toxin-antitoxin (TA) systems consist of stable toxic proteins that are held in check by co-expression of labile antitoxin molecules, the nature of which distinguishes three classes of TA systems [1,2]
It has long been hypothesized that TA systems contribute to bacterial pathogenesis, but clear-cut phenotypes associated with any individual TA system have not been described
We demonstrate that distinct subsets of TA systems are linked with a major group of bacterial pathogens known as Extraintestinal Pathogenic E. coli (ExPEC)

Summary

Introduction

Toxin-antitoxin (TA) systems consist of stable toxic proteins that are held in check by co-expression of labile antitoxin molecules, the nature of which distinguishes three classes of TA systems [1,2]. Antitoxins made by type I TA loci are small antisense RNAs that suppress translation of the toxin genes [3], while the antitoxins encoded by type II and type III TA loci are, respectively, proteins and small RNAs that complex with and inactivate their cognate protein toxins [2,4]. TA systems were initially characterized as plasmidencoded genes that serve as addiction molecules, promoting the heritable maintenance of extra-chromosomal DNA within a bacterial population [10,11]. The functional relevance of individual chromosomally encoded TA systems to bacterial fitness within the environment is oftentimes ambiguous, and even less understood is the impact of these systems on bacterial pathogenesis [12,13]

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