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Fig. 1. Generalized scheme for an acyl-HSL quorum-sensing circuit in a bacterial cell. The orange square indicates an acyl-HSL synthase-Luxl homolog. The diamonds are a LuxR homolog. Yellow diamonds on the bacterial chromosome are the LuxR homolog activated by the acyl-HSL signal. The arrows on the chromosome are qsc genes. The acyl-HSL (AHSL) signal can diffuse in and out of cells. The compound in the box is an acyl-HSL (R1, H, OH, or O; R2, (CH 2)2-14, or ). The substrates for the acyl-HSL synthase are an acylated acyl carrier protein (Acyl-ACP) and S-adenosylmethionine (SAM).

organ symbiosis with certain marine animals (20, 21). Here quorum sensing is critical to the symbiosis. Acyl-HSL signaling is critical for virulence of the plant pathogen Erwinia carotovora (22) and for virulence of P. aeruginosa in mouse models of lung (23) and burn infections (24), in invertebrates (25, 26 and 27), and in plants (28). Thus acyl-HSL quorum sensing appears as a common theme in the interaction of several different bacterial species with eukaryotic hosts. We will describe the elements of quorum sensing, and discuss some of the factors controlled by quorum sensing in P. aeruginosa. In this paper P. aeruginosa will serve as a model for the role of bacterial communication in community behaviors important in pathogenesis.

Quorum Sensing in P. aeruginosa

P. aeruginosa can be isolated from soil and water. It is also an opportunistic pathogen of humans, other animals, and plants. One of the reasons P. aeruginosa is a successful opportunistic pathogen is that it produces a battery of secreted virulence factors. These virulence factors include exoproteases, siderophores, exotoxins, and lipases. Many of these virulence factors are regulated by quorum sensing (for reviews see refs.1, 29, and 30). Of what advantage to P. aeruginosa is quorum sensing control of virulence factors? First, it is economical to produce extracellular factors only after a critical population has been achieved. A mass of cells is required to produce sufficient quantities of these factors to influence the surrounding environment. Furthermore, in the host, timing of the deployment of virulence factors may be critical. The pathogen can amass without displaying its virulence factors, and then the pathogen can mount a surprise attack in which the arsenal of virulence factors is deployed in a coordinated and overwhelming fashion.

Genetic studies have revealed two quorum-sensing systems in P. aeruginosa. Both of these systems, LasR-I and RhlR-I, have linked R and I genes. They are the quorum-sensing systems (31, 32, 33, 34, 35 and 36). In addition, the recently completed P. aeruginosa genome sequencing project has revealed a third LuxR homolog that is adjacent to a cluster of quorum-sensing-controlled (qsc) genes (37). However, a third LuxI homolog is not evident from the sequence, and the function of the third LuxR homolog is as yet unknown. LasR is a transcriptional regulator that responds primarily to the LasI-generated signal, 3OC12-HSL, and RhlR is a transcriptional regulator that responds best to the RhlI-generated signal, C4-HSL. The current model for quorum sensing in P. aeruginosa is as follows: at low population densities LasI produces a basal level of 3OC12-HSL. As density increases, 3OC12-HSL builds to a critical concentration, at which point it interacts with LasR. This LasR-3OC12-HSL complex then activates transcription of a number of genes. The list of target genes includes lasB, toxA, rhlR, and lasI (29, 32, 36, 38, 39). A curious fact is that different target genes are activated at different 3OC12-HSL concentrations (39). Activation of lasI by LasR creates a positive autoregulatory loop. The activation of rhlR by LasR results in a quorum-sensing regulatory cascade, in which activation of the rhl system requires an active las system. RhlR responds best to the RhlI-generated C4-HSL. RhlR then activates expression of genes required for production of a variety of secondary metabolites such as hydrogen cyanide and pyocyanin (for a review see ref.29). A DNA sequence with dyad symmetry called a lux-box-like sequence can easily be identified in the promoter regions of many quorum-sensing-controlled (qsc) genes (10, 37, 40, 41). By analogy to other acyl-HSL quorum-sensing systems we deduce that the lux-box-like sequences function as binding sites for LasR and RhlR. It is not yet clear how RhlR and LasR discriminate between their respective binding sites. In fact, many genes show partial activation with either LasR or RhlR and the appropriate acyl-HSL (for example see refs.30 and 37). One explanation for the partial activation or incomplete specificity is that binding site discrimination is less than perfect and either LasR or RhlR can bind with varying efficiency to any lux-box-like element. However, lux-box-like sequences are not apparent in the promoter regions of all qsc genes. This observation suggests that LasR or RhlR may also bind to identified sequences, or that some qsc genes are controlled by LasR or RhlR indirectly.

As discussed above, many genes have been reported to come under the control of quorum sensing in P. aeruginosa. For some genes such as lasB there is a considerable amount of evidence in support of this conclusion (36, 38). For other genes, the data are limited, and in many cases the degree of transcriptional control reported is low. A recent study used a random mutagenesis approach to identify 39 genes that were highly regulated (minimum 5-fold induction, maximum 740-fold induction) by quorum sensing (37). The genes were divided into four different classes, two of which respond to 3OC12-HSL, and two of which required both C4-HSL and 3OC12-HSL for maximal induction. The qsc genes map throughout the P. aeruginosa chromosome (Fig. 2), confirming the view that quorum sensing in this bacterium represents a global regulatory system (29). The 39 genes revealed by the random mutagenesis study represent only a subset of the qsc genes in P. aeruginosa. It was estimated that as many as 4% of the roughly 6,000 P. aeruginosa genes are controlled by quorum sensing (37).

One report indicates that transcription of rpoS, a gene encoding an RNA polymerase σ subunit involved in expression of stationary-phase factors, is activated by RhlR and C4-HSL (42). This finding raises the possibility that many genes may be controlled indirectly rather than directly by quorum sensing. It is also an enticing hypothesis because it lends itself to the idea that one specific cue that enables a cell to anticipate stationary phase is crowding. Unfortunately, quorum-sensing control of rpoS transcription is an example for which there is limited evidence. It is also an example for which there are low levels of induction (at best 3-fold). In fact, recent investigations suggest that quorum sensing may have no significant influence on rpoS transcription in P. aeruginosa (43).



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