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Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli.

ABSTRACT: Two-component systems (TCSs) dictate many bacterial responses to environmental change via the activation of a membrane-embedded sensor kinase, which has molecular specificity for a cognate response regulator protein. However, although the majority of TCSs operate through seemingly strict cognate protein-protein interactions, there have been several reports of TCSs that violate this classical model of signal transduction. Our group has recently demonstrated that some of these cross-interacting TCSs function in a manner that imparts a fitness advantage to bacterial pathogens. In this study, we describe interconnectivity between the metabolite-sensing TCSs YpdA/YpdB and BtsS/BtsR in uropathogenic Escherichia coli (UPEC). The YpdA/YpdB and BtsS/BtsR TCSs have been previously reported to interact in K12 E. coli, where they alter the expression of putative transporter genes yhjX and yjiY, respectively. These target genes are both upregulated in UPEC during acute and chronic murine models of urinary tract infection, as well as in response to pyruvate and serine added to growth media in vitro. Here, we show that proper regulation of yhjX in UPEC requires the presence of all components from both of these TCSs. By utilizing plasmid-encoded luciferase reporters tracking the activity of the yhjX and yjiY promoters, we demonstrate that deletions in one TCS substantially alter transcriptional activity of the opposing system's target gene. However, unlike in K12 E. coli, single gene deletions in the YpdA/YpdB system do not alter yjiY gene expression in UPEC, suggesting that niche and lifestyle-specific pressures may be selecting for differential cross-regulation of TCSs in pathogenic and non-pathogenic E. coli.

SUBMITTER: Steiner BD

PROVIDER: S-EPMC5834395 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli.

Steiner Bradley D BD Eberly Allison R AR Hurst Melanie N MN Zhang Ellisa W EW Green Hamilton D HD Behr Stefan S Jung Kirsten K Hadjifrangiskou Maria M

The Journal of membrane biology 20180127 1

Two-component systems (TCSs) dictate many bacterial responses to environmental change via the activation of a membrane-embedded sensor kinase, which has molecular specificity for a cognate response regulator protein. However, although the majority of TCSs operate through seemingly strict cognate protein-protein interactions, there have been several reports of TCSs that violate this classical model of signal transduction. Our group has recently demonstrated that some of these cross-interacting TC ...[more]

PMID: 29374286

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Project description:Uropathogenic Escherichia coli (UPEC) is the leading cause of human urinary tract infections (UTIs), and many patients experience recurrent infection after successful antibiotic treatment. The source of recurrent infections may be persistent bacterial reservoirs in vivo that are in a quiescent state and thus are not susceptible to antibiotics. Here, we show that multiple UPEC strains require a quorum to proliferate in vitro with glucose as the carbon source. At low cell density, the bacteria remain viable but enter a quiescent, nonproliferative state. Of the clinical UPEC isolates tested to date, 35% (51/145) enter this quiescent state, including isolates from the recently emerged, multidrug-resistant pandemic lineage ST131 (i.e., strain JJ1886) and isolates from the classic endemic lineage ST73 (i.e., strain CFT073). Moreover, quorum-dependent UPEC quiescence is prevented and reversed by small-molecule proliferants that stimulate colony formation. These proliferation cues include d-amino acid-containing peptidoglycan (PG) tetra- and pentapeptides, as well as high local concentrations of l-lysine and l-methionine. Peptidoglycan fragments originate from the peptidoglycan layer that supports the bacterial cell wall but are released as bacteria grow. These fragments are detected by a variety of organisms, including human cells, other diverse bacteria, and, as we show here for the first time, UPEC. Together, these results show that for UPEC, (i) sensing of PG stem peptide and uptake of l-lysine modulate the quorum-regulated decision to proliferate and (ii) quiescence can be prevented by both intra- and interspecies PG peptide signaling.IMPORTANCE Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs). During pathogenesis, UPEC cells adhere to and infiltrate bladder epithelial cells, where they may form intracellular bacterial communities (IBCs) or enter a nongrowing or slowly growing quiescent state. Here, we show in vitro that UPEC strains at low population density enter a reversible, quiescent state by halting division. Quiescent cells resume proliferation in response to sensing a quorum and detecting external signals, or cues, including peptidoglycan tetra- and pentapeptides.

Project description:Siderophores are secreted ferric ion chelators used to obtain iron in nutrient-limited environmental niches, including human hosts. While all Escherichia coli express the enterobactin (Ent) siderophore system, isolates from patients with urinary tract infections additionally express the genetically distinct yersiniabactin (Ybt) siderophore system. To determine whether the Ent and Ybt systems are functionally redundant for iron uptake, we compared the growth of different isogenic siderophore biosynthetic mutants in the presence of transferrin, a human iron-binding protein. We observed that Ybt expression does not compensate for deficient Ent expression following low-density inoculation. Using transcriptional and product analysis, we found this non-redundancy to be attributable to a density-dependent transcriptional stimulation cycle in which Ybt functions as an autoinducer. These results distinguish the Ybt system as a combined quorum-sensing and siderophore system. These functions may reflect Ybt as a public good within bacterial communities or as an adaptation to confined, subcellular compartments in infected hosts. This combined functionality may contribute to the extraintestinal pathogenic potential of E. coli and related Enterobacterales.IMPORTANCEPatients with urinary tract infections are often infected with Escherichia coli strains carrying adaptations that increase their pathogenic potential. One of these adaptations is the accumulation of multiple siderophore systems, which scavenge iron for nutritional use. While iron uptake is important for bacterial growth, the increased metabolic costs of siderophore production could diminish bacterial fitness during infections. In a siderophore-dependent growth condition, we show that the virulence-associated yersiniabactin siderophore system in uropathogenic E. coli is not redundant with the ubiquitous E. coli enterobactin system. This arises not from differences in iron-scavenging activity but because yersiniabactin is preferentially expressed during bacterial crowding, leaving bacteria dependent upon enterobactin for growth at low cell density. Notably, this regulatory mode arises because yersiniabactin stimulates its own expression, acting as an autoinducer in a previously unappreciated quorum-sensing system. This unexpected result connects quorum-sensing with pathogenic potential in E. coli and related Enterobacterales.

Dataset Information

Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli.

Publications

Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli.

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