Quorum sensing in P. aeruginosa

One reason for the versatility of P. aeruginosa, is that it produces a large battery of virulence determinants including elastase, LasA protease, alkaline protease, rhamnolipids, type IV pilus-mediated twitching motility, pyoverdin (Williams et al., 1996, Stintzi et al., 1998, Glessner et al., 1999, Pesci & Iglewski, 1999), pyocyanin (Brint & Ohman, 1995, Reimmann et al., 1997) and the cytotoxic lectins PA-I and PA-II (Winzer et al., 2000). It is now known that many of these virulence determinants are regulated at the genetic level in a cell density-dependent manner through quorum sensing. P. aeruginosa possesses at least two quorum sensing systems, namely the las and rhl (vsm) systems which comprise of the LuxRI homologues LasRI (Gambello & Iglewski, 1991) and RhlRI (VsmRI) (Ochsner et al., 1994, Latifi et al., 1995) respectively. LasI directs the synthesis of 3-oxo-C12-HSL (Passador et al., 1993, Pearson et al., 1994) whereas RhlI directs the synthesis of C4-HSL) (Winson et al., 1995). The las and the rhl systems are thought to exist in a hierarchy where the las system exerts transcriptional control over RhlR (Williams et al., 1996, Pesci et al., 1997). The transcriptional activator LasR functions in conjunction with 3-oxo-C12-HSL to regulate the expression of the genes encoding for the virulence determinants elastase, LasA protease, alkaline protease and exotoxin A (Gambello & Iglewski, 1991, Toder et al., 1991, Gambello et al., 1993, Pearson et al., 1994) as well as lasI. LasI directs the synthesis of 3-oxo-C12-HSL which together with LasR, binds to the lasI promoter and creates a positive feedback system. The RhlR transcriptional activator, along with its cognate AHL (C4-HSL), regulates the expression of rhlAB (rhamnolipid), lasB, aprA, RpoS, cyanide, pyocyanin and the lectins PA-I and PA-II (Ochsner et al., 1994, Brint & Ohman, 1995, Latifi et al., 1995, Pearson et al., 1995, Winson et al., 1995, Latifi et al., 1996, Winzer et al., 2000). These exist in a hierarchical manner where by the LasR/3-oxo-C12-HSL regulates rhlR (Latifi et al., 1996, Pesci et al., 1997) and consequently both systems are required for the regulation of all the above virulence determinants.

In addition to 3-oxo-C12-HSL and C4-HSL, P. aeruginosa releases a 4-quinolone signal molecule into the extracellular milieu, the synthesis and bioactivity of which has been reported to be mediated via the las and rhl systems respectively. This molecule has been chemically identified as 2-heptyl-3-hydroxy-4(1H)-quinolone and termed the Pseudomonas Quinolone Signal (PQS) (Pesci et al., 1999). LasR has been shown to regulate PQS production and the provision of exogenous PQS induces expression of lasB (coding for elastase), rhlI and rhlR (Pesci et al., 1999; McKnight et al., 2000) suggesting that PQS activity constitutes a regulatory link between the las and rhl quorum sensing systems. However, McKnight et al., (2000) suggested that PQS is not involved in sensing cell density as it was identified much later in the growth cycle than is typical for a quorum sensing signal molecule. It was speculated that the purpose of PQS in regulating rhlI expression, may be to further up-regulate the rhl quorum sensing system in late stationary phase cultures. Interestingly, PQS has recently been isolated from the lungs of CF patients infected with P. aeruginosa (Collier et al., 2002; Guina et al., 2003). The regulation of PQS synthesis is becoming better understood. Calfee et al., (2001) demonstrated that anthranilate is a precursor of PQS and that inhibition of anthranilate results in a loss of PQS production. More recently, the structural genes required for PQS have been identified (pqsABCDH) along with a transcriptional regulator (pqsR) and a response effector (pqsE) (Gallagher et al., 2002). The transcription of pqsH is regulated by the las quorum sensing system, linking quorum sensing and PQS regulation. However, it has also been shown that PQS can be produced in the absence of LasR (Diggle et al., 2003). Furthermore, it has been demonstrated that PQS is essential for the activation of certain rhl-dependent genes (Diggle et al., 2003).

Download a diagram of the Pseudomonas aeruginosa quorum sensing hierarchy