Review
A network of networks: Quorum-sensing gene regulation in Pseudomonas aeruginosa

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Abstract

The opportunistic pathogen Pseudomonas aeruginosa possesses two N-acyl-homoserine lactone quorum-sensing systems that regulate large, overlapping sets of genes. Recent global transcriptome and proteome analyses provided a wealth of information about the identity of the regulated genes, N-acyl-homoserine lactone signal specificity, timing of induction, and environmental effects on gene expression. Quorum-sensing gene expression in P. aeruginosa is also embedded in a highly interconnected network of other regulatory systems with a high potential for integrating and responding to multiple environmental signals. Such epigenetic complexity may constitute the basis for the exceptional adaptibility of P. aeruginosa to diverse environments.

Introduction

Pseudomonas aeruginosa is a ubiquitous, metabolically versatile bacterium that thrives in diverse terrestrial and aquatic environments. It also has the important capability of transition from its environmental habitats to become an opportunistic pathogen of several lower eukaryotes, plants and animals. In immunocompromised humans, it causes a wide variety of acute and persistent infections characterized by their resistance to antibiotic treatment (Costerton, 2001; Lyczak et al., 2000).

The completion of the P. aeruginosa genome sequence provided a first global insight into the basis for the bacterium's versatility and resilience (Stover et al., 2000). The comparatively large genome contains an overwhelming number of genes (up to 10% of the predicted 5570 genes) that are thought to encode regulators of gene expression, prime candidates for the orchestration of adaptive responses. The subsequent availability of high-density DNA microarrays has provided the Pseudomonas research community with a tool to decipher the underlying transcription networks (Goodman and Lory, 2004). Quorum sensing (QS) is one such global regulatory mechanism employed by P. aeruginosa to regulate hundreds of genes, among them many virulence factors, in response to population size. This review highlights the advances made in understanding P. aeruginosa QS through functional genomics.

Section snippets

The P. aeruginosa quorum-sensing circuitry

In bacterial QS, bacteria sense and respond to their population density via self-produced small diffusible molecules. In P. aeruginosa and many other Gram-negative bacteria, these signal molecules are N-acylated homoserine lactones (acyl-HSL). The signals, produced by LuxI-type signal synthases, accumulate as the population density increases. At a certain threshold concentration they bind to LuxR-type receptors that function as activators of gene expression.

P. aeruginosa possesses two acyl-HSL

Global identification of quorum sensing-regulated genes and proteins

Since the discovery of cell-cell signaling in P. aeruginosa in the early 1990s (Passador et al., 1993), the list of genes reported to be controlled by QS has increased steadily. A first global approach to identify a larger set of quorum-controlled genes was taken by Whiteley et al. (1999). They generated random lacZ transcriptional fusions in the chromosome of a lasI rhlI signal generation mutant, and screened the resulting library for acyl-HSL-dependent induction of β-galactosidase. Overall,

Quorum-controlled promoters and signal specificity

The transcriptome analysis by Schuster et al. (2003) allowed further insights into the signal requirements for the activation of individual quorum-controlled genes. Comparison of the gene expression profiles of a signal generation mutant in the presence of 3OC12-HSL alone and in the presence of both signals, 3OC12-HSL and C4-HSL, revealed that signal specificities are on a continuum (Fig. 2). Some genes respond no better to both signals than to 3OC12-HSL alone (“las-specific” genes), most genes

Quorum-sensing gene induction is not related to signal concentration

The genome-scale studies described above revealed that P. aeruginosa QS is a global regulatory system that affects many different cellular functions. It has also become evident that the QS system itself is embedded in a network of global regulation. Studies with reporter gene fusions showed that several quorum-controlled genes exhibit a delayed response to exogenously added acyl-HSL signals until the stationary phase of growth (Diggle et al., 2002; Whiteley et al., 1999; Winzer et al., 2000).

Conclusions

P. aeruginosa QS represents one of the best understood cell-cell communication systems in bacteria. Two intertwined acyl-HSL signaling systems control the expression of hundreds of target genes. The wealth of data from whole genome studies has allowed us to unify results previously observed only for few individual QS genes. It has provided insights into global response patterns with respect to signal specificity, timing of gene expression, and growth conditions. It has broadened our

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