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Review |
1 School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia
2 Institute for Eye Research, Sydney, Australia
3 Vision CRC, Sydney, Australia
4 BioScience and Technology, The Technical University of Denmark, DK-2800 Lyngby, Denmark
5 School of Biotechnology and Biomolecular Sciences and The Centre for Marine Bio-Innovation, University of New South Wales, Sydney, NSW 2052, Australia
Correspondence
S. A. Rice
Scott.Rice{at}unsw.edu.au
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ABSTRACT |
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 TOP ABSTRACT IntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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Present address: School of Biological Sciences, University of Southampton, Southampton SO17 IBJ, UK.
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Introduction |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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This review presents a comparison of the role of QS in two infection types, microbial keratitis and chronic lung infections. Although these infection types appear to be distinct, one being characterized as an acute infection and the other typically more chronic in nature, they share some common features. Both sites of infection are mucosal tissues that have limited microbial flora in the absence of infection. P. aeruginosa is one of the most important infecting bacteria for each tissue, and QS plays a role in the infection process in both cases. The QS system of P. aeruginosa, QS-regulated virulence factors and the effect of QS signals on the host are presented as background to the subsequent sections that specifically relate to QS in microbial keratitis and chronic lung infections.
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QS as a global regulator of gene expression |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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; Pearson et al., 1994; Preston et al., 1997). As noted above, the AHL QS system is present in many Gram-negative proteobacteria and has been identified in a range of human, animal and plant pathogens. Of these organisms, P. aeruginosa is one of the most intensively studied due to its significant impacts on human health and inherent difficulty to treat. DNA microarray studies have demonstrated that QS controls the expression of somewhere between 3 and 10 % of the genome of P. aeruginosa (Hentzer et al., 2003; Schuster et al., 2003; Wagner et al., 2003); many of these genes either directly mediate the pathogenicity of P. aeruginosa, or play significant roles in the persistence of the organism during infection, mainly by contributing to the formation of biofilms that are able to withstand the action of the immune system.
There are two hierarchically arranged QS circuits within P. aeruginosa that are able to respond to AHL signals. The primary system is the Las system, which encodes the proteins LasI and LasR (Gambello & Iglewski, 1991). The LasI protein catalyses the production of the AHL molecule N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL) (Pearson et al., 1994). The 3O-C12-HSL molecule docks with the DNA-binding transcription regulator LasR, which allows LasR to bind to the promoters of QS-regulated genes to control virulence factor production, including such genes as lasB (elastase), lasA (staphylolysin), aprA (alkaline protease), toxA (exotoxin A), hcnABC (hydrogen-cyanide synthase) and lasI itself (Chapon-Herve et al., 1997; Gambello & Iglewski, 1991; Gambello et al., 1993; Passador et al., 1993; Pessi & Haas, 2000; Seed et al., 1995; Storey et al., 1998; Toder et al., 1991, 1994). The Las circuit induces a positive feedback loop to produce more AHL, and also induces a secondary QS circuit, the Rhl system (Pearson et al., 1995; Seed et al., 1995).
The Rhl system consists of RhlI, which synthesizes N-butyryl-L-homoserine lactone (C4-HSL) (Brint & Ohman, 1995; Pearson et al., 1997) and the receptor, RhlR (Ochsner et al., 1994; Pearson et al., 1995). As with the Las system, C4-HSL accumulates to a sufficient concentration and binds to RhlR. The Rhl system induces expression of rhlAB (rhamnolipid synthesis genes), rhlI, lasB, rpoS (the stationary-phase sigma factor), lecA (type-1 lectin), lecB (type-II lectin), hcnABC and genes involved in pyocyanin production (Brint & Ohman, 1995; Latifi et al., 1995; Ochsner et al., 1994; Pearson et al., 1997; Pessi & Haas, 2000; Winzer et al., 2000).
The Pseudomonas quinolone signal (PQS) is a third P. aeruginosa QS signal that is dependent on the balanced production of 3O-C12-HSL and C4-HSL (Pesci et al., 1999). The PQS molecule (2-heptyl-3-hydroxy-4-quinolone) plays a significant role in the transcription of Rhl-dependent P. aeruginosa virulence genes such as those encoding production of pyocyanin and rhamnolipid (Deziel et al., 2004). PQS production is intimately linked to the QS hierarchy, with its production and bioactivity requiring both the las and rhl QS systems (McGrath et al., 2004). Additionally, PQS was recently shown to be solubilized by rhamnolipids, the production of which is controlled by the Rhl system (Wade et al., 2005), which may be important for the activity of PQS as an extracellular signal. Thus, it is clear that QS controls a significant proportion of the arsenal of virulence factors used by P. aeruginosa to mediate infection. This dependence on QS as a key regulator of virulence factor production may represent the Achilles heel of P. aeruginosa, which can be exploited to control infection.
Additional genes can influence the QS response. For example, the QS regulator (QscR) was discovered as a repressor of 3O-C12-HSL-regulated virulence factors; it ensures that the QS cascade is not activated prematurely within a host, or in environments where it is not required (Chugani et al., 2001). This inhibitory effect is controlled by the global activator protein GacA (Ledgham et al., 2003; Reimmann et al., 1997). RsaL, the product of a gene found between lasI and lasR in the P. aeruginosa PAO1 genome, is a negative regulator of the Las QS circuit (de Kievit et al., 1999). The product of the vrf gene is a cAMP receptor homologue that is required for the transcription of lasR (Albus et al., 1997; West et al., 1994). RsmA has been shown to downregulate several QS-dependent phenotypes in P. aeruginosa, such as protease, elastase and staphylolytic activities along with the production of a cytotoxic lectin, hydrogen cyanide and pyocyanin. Overexpression of RsmA also resulted in reduced expression of the AHL synthase genes lasI and rhlI (Pessi et al., 2001). Furthermore, it has been shown that RpoN controls the expression of rhlI (Heurlier et al., 2003; Thompson et al., 2003).
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The role of QS in microbial keratitis |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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). With 80–140 million contact lens wearers worldwide, this represents a significant risk to sight. MK is a frank infection of the cornea characterized by replicating microbes in the tissue and infiltration of the tissue by white blood cells, especially polymorphonuclear leukocytes (PMNs), and can lead to eventual loss of sight. Wearing contact lenses is a primary risk factor for MK, and P. aeruginosa remains the most common cause of infection, accounting for around 40–70 % of isolates (Willcox et al., 2002).
Identification of QS signals and regulated products from clinical specimens and isolates
All ocular isolates from cases of infectious MK contain lasI, lasR, rhlI and rhlR (Zhu et al., 2004) and the majority produce C4-HSL, 3O-C12-HSL and C6-HSL (Zhu et al., 2002). In contrast, of the P. aeruginosa isolates from non-infective events from the eye, just under half appeared to have lost one or more las or rhl genes, and two that had lost the rhlI gene had also lost the rhlAB gene (Zhu et al., 2004). Furthermore, invasive strains of P. aeruginosa (exoS-positive) isolated from keratitis patients produced more AHL signal molecules, in terms of types and concentrations, compared with the amount produced by cytotoxic strains (Zhu et al., 2002).
In MK, lasI or rhlI QS-deficient strains are not able to induce corneal infection in the mouse model (Fig. 1; Zhu et al., 2004), highlighting the importance of QS systems, particularly the possession of functional lasI or rhlI genes. The virulence of the mutants was fully restored by complementation with a functional lasI or rhlI gene, respectively (Fig. 1; Zhu et al., 2004). However, single mutations in either lasR or rhlR mutants did not show statistically significant reductions in virulence in the eye, despite there being a reduction in bacterial numbers in the eye with the lasR mutant (Zhu et al., 2004). These results are in agreement with a previous report where there was no significant difference reported between the 50 % infective doses of PAO1 and its lasR mutant during corneal infection (Preston et al., 1997). It is also possible that the AHL signals (especially 3O-C12-HSL) may make a significant contribution to virulence, e.g. through immune modulation.
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), elastase (lasB; Kessler & Blumberg, 1987), alkaline protease (aprA; Twining et al., 1993) and protease IV (prpL; Engel et al., 1997; O'Callaghan et al., 1996; Traidej et al., 2003). There is good evidence that QS is involved in the upregulation of the genes lasB, aprA and prpL and it may be that the Las system is particularly involved in this activation (Nouwens et al., 2003). The Rhl system has been shown to repress the production of exoS (Hogardt et al., 2004). There is currently no evidence for a direct role of QS in regulation of exoU, but the Rhl system can downregulate the type III secretion system in the absence of Ca2+ (Bleves et al., 2005). Therefore, a functional Rhl system would likely result in the reduced secretion of ExoU and other type III secretion system toxins such as ExoT and ExoS, and thus reduce pathogenicity associated with these factors. Perhaps initial infection by small numbers of cells is not QS dependent and so ExoU/ExoS/ExoT are active and the bacterial cells can disrupt host cells (either via invasion or a cytotoxic effect). The type III toxins are then silenced during later stages of infection when larger numbers of cells are present and action of proteases is perhaps more important for cell survival. While the role of QS and type III secretion remains to be elucidated, there is clear evidence that other QS-controlled virulence factors, such as lasB, are important for eye infections.
AHL effects on the ocular immune response
The lack of infection caused by lasI mutants could be due to direct effects of 3O-C12-HSL, which can stimulate an immune response (Smith et al., 2002) or disrupt epithelial cells' barrier function (Vikstrom et al., 2006). It is often the host immune response which results in severe corneal damage, including perforation of the globe and blindness (Hazlett et al., 1992; Hazlett, 2005; Laibson, 1990). Corneal epithelial cells with intact barrier function appear to be resistant to infection by P. aeruginosa (Hazlett et al., 1978, 1980). Therefore if 3O-C12-HSL is able to alter the barrier function of corneal epithelial cells, as has been demonstrated for colon cells, it may provide an entry into the cornea for the bacterium and thus the AHLs could represent virulence factors in their own right. This may partially explain the observation that strains lacking the lasI AHL synthase have reduced virulence, while lasR mutants are only minimally affected in virulence. However, the apparent lack of immune stimulation by C4-HSL (Shiner et al., 2006; Smith et al., 2002; Zimmermann et al., 2006) argues that the loss of virulence observed for the rhlI mutant is likely to be dependent on a mechanism other than direct effects of the C4-HSL on the immune system. Interestingly, it has been reported that interferon-
(IFN-) can be sensed by the outer-membrane protein OprF of P. aeruginosa, which results in the expression of QS-controlled genes (Wu et al., 2005), and this links QS to the Th1/Th2 dichotomy involved in MK. The Th1 response is associated with high levels of IFN- and susceptibility of the cornea to perforation following infection with P. aeruginosa, whereas the Th2 response is associated with resistance to perforation (Hazlett et al., 2000; Hazlett, 2005). Thus the increased pathology seen in Th1/IFN-producing mice might be caused not only directly by the immune response, but indirectly by the immune response upregulating virulence factors of P. aeruginosa by stimulating their production through the AHL pathway(s).
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QS in chronic lung infections |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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Identification of QS signals and regulated products from clinical specimens and isolates
It has been well established that AHL-mediated QS is active in the lungs of CF patients. For example, AHLs have been detected in sputum samples and lung extracts of CF patients (Erickson et al., 2002; Geisenberger et al., 2000) and it has been shown that QS-regulated genes are upregulated in CF samples (Storey et al., 1998). Analysis of a clonal lineage of P. aeruginosa from CF patients in Australia showed that all strains contained genes rhlI/rhlR and 42/43 strains retained genes lasI/lasR (Tingpej et al., 2007). QS has also been shown to affect biofilm tolerance to antibiotics (Davies et al., 1998; Hentzer et al., 2003), and the ratio of C4-HSL to 3O-C12-HSL detected in the lungs has been used to support the hypothesis that P. aeruginosa is present in the lungs in a biofilm (Singh et al., 2000). Given the high numbers of P. aeruginosa reported in sputum, ranging from 106 to 1010 c.f.u. ml–1 (Giwercman et al., 1990), it is not surprising that QS is active or that biofilms form in the lungs of CF patients. The quinolone signal, PQS, can also be detected in the lungs of CF patients (Collier et al., 2002), further supporting an active role of QS in chronic lung infections.
In vivo studies of acute and chronic lung infections using QS mutants have shown that QS signal synthase mutants (either mutations in lasI or rhlI or double mutants) were less virulent than the isogenic wild-type parental strains (Hoffmann et al., 2005; Pearson et al., 2000; Smith et al., 2002; Wu et al., 2001). It has also been demonstrated that loss of the HSL receptor genes (lasR/rhlR) results in strains that are less able to colonize and infect the lungs. As shown in Fig. 2, there was a significant reduction in the number of bacteria recovered from the lungs of mice infected with a QS mutant (
lasR-rhlR) of P. aeruginosa compared to the isogenic wild-type (Bjarnsholt et al., 2005). Furthermore, an infection model based on the implantation of silicone chips pre-colonized with P. aeruginosa into lungs of mice has also demonstrated that a functional QS system is critical for the establishment of infection (Christensen et al., 2007). However, a number of studies have demonstrated that QS mutants can be isolated from CF samples. Frequencies of QS mutants ranged from 3 % (6 out of 200 isolates) to 50 % (3 of 6 isolates tested; reviewed by Heurlier et al., 2006). Whole-genome sequencing of early- and late-stage isolates of P. aeruginosa from a CF patient showed that lasR was inactivated in the late-stage infection isolate (Smith et al., 2006). In a follow-up study, comparing isolates from the same patient over an 8 year period, lasR mutants could be detected in isolates obtained after approximately 2 years of infection (D'Argenio et al., 2007). However, wild-type strains could also be detected until approximately 5 years post-infection, after which time all of the isolates tested carried a single lasR mutation, suggesting that loss of LasR occurs over time (D'Argenio et al., 2007). The clonal lineage of P. aeruginosa strains from Australia, whilst retaining QS genes, often do not produce the QS signals, at least in vitro (Tingpej et al., 2007). One of the interesting observations from these studies has been that the majority of mutations leading to loss of QS have been found in lasR, with few mutations in the AHL synthase genes (lasI or rhlI). The explanation for the predominance of lasR mutants that are isolated from long-term infected CF patients remains elusive. It has been proposed that loss of LasR might confer an adaptive or growth advantage in the lung, especially when the bacteria are growing on amino acids as carbon sources (D'Argenio et al., 2007). Alternatively, it is possible that the lasR mutants are over-represented in the dispersal population and hence are more likely to be observed. The lower frequency of isolation of rhl mutants may indicate that this part of the QS system plays an important role in long-term infection or colonization, which may be mediated through the role of the rhl system in regulating rhamnolipid production (see below). Thus, the loss of QS in chronic lung infections may reflect a change in strategy away from virulence and more towards persistence (Smith et al., 2006), where an established strain, in a biofilm, may no longer require or benefit from the production of high levels of virulence factors. This latter concept may partly explain the difference in appearance of QS mutants between eye infections and lung infections. For MK (above), all clinical isolates tested, where pathology was noted, were QS competent, and QS mutants were only detected in isolates from eyes without infections. Thus, infection of the eye may represent a more acute infection, dependent on the expression of specific virulence factors, whilst lung infection selects for strains with a long-term maintenance strategy, where high levels of virulence factors are not produced after the initial acute phase and colonization.
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). Shaver & Hauser (2004) demonstrated that for acute lung infections, mutants deficient in the production of ExoS or ExoU were less virulent than their isogenic wild-type, and the exoU mutant was the least virulent of the two. Strains isolated from patients carried either exoU or exoS, but not both, and CF isolates were more frequently exoS positive (Feltman et al., 2001; Tingpej et al., 2007). This latter finding contrasts with isolates from MK, where there is an approximately equal likelihood of isolating either exoS- or exoU-containing strains (Zhu et al., 2006). As noted above, the QS system has been shown to regulate the production of the type III secretion system (Bleves et al., 2005; Hogardt et al., 2004), but does not appear to directly control expression of the effector proteins, such as ExoS or ExoU. Thus, the role of QS in the secretion of these toxins is indirect. The frequency of strains that are capable of type III mediated secretion appears to decrease as the length of time of CF infection increases: in one study approximately 49 % of isolates from recently infected patients were positive compared to 18 % for isolates from chronically infected patients (Jain et al., 2004). Corech et al. (2005) reported that type III secretion components could be detected during early infection in children, suggesting a role for type III secretion during the initial colonization stages of infection. Antibodies directed at proteins involved in the type III secretion pathway were protective to the host (Sawa et al., 1999), and hence it may be to the long-term benefit of colonizing strains to reduce expression of these virulence factors; this again supports the hypothesis that chronic lung infection may reflect a shift away from overt virulence towards one of quiet persistence. In contrast, Moss et al. (2001) detected antibodies for ExoS and the type III secretion system in chronically infected patients (Moss et al., 2001). Thus, it remains to be determined whether QS regulation of the type III secretion system is an important factor determining chronic infection in CF patients. It should be noted, however, that there is evidence that QS-regulated genes are important in lung infection. Erickson et al. (2002) demonstrated that the QS-regulated gene lasB, encoding the virulence factor elastase (LasB), was expressed in the lungs of chronically infected patients. This observation is supported by data showing that elastase activity is commonly detected in the lungs of CF patients and that elastase mutants were less virulent (Azghani et al., 2000). The QS-regulated virulence factor pyocyanin is present in relatively high concentrations in the sputum of infected patients, contributing to the greenish colour of such sputa, and acts to inhibit the activity of cilia in the respiratory mucosa (Wilson et al., 1988). Mutants defective in pyocyanin production were more effectively cleared from the lungs of infected mice (2–3 log reduction) than the wild-type (1.4 log increase) (Lau et al., 2004). In addition to directly causing tissue destruction, elastase also protects P. aeruginosa during infection by degrading immunoglobulins and complement proteins (Bainbridge & Fick, 1989; Cripps et al., 1995). Another class of QS-controlled product that affects the immune system is rhamnolipids, bioactive molecules with surfactant properties, synthesized by RhlAB, with the most abundant being L-rhamnosyl-3-hydroxydecanoyl-3-hydroxydecanoate (rhamnolipid 1) and 2-O-
-L-rhamnopyranosyl--L-rhamnopyranosyl-β-hydroxydecanoyl-β-hydroxydecanoic acid (rhamnolipid 2, also referred to as rhamnolipid B by Jensen et al., 2007; Lang & Wullbrandt, 1999; Maier & Soberon-Chavez, 2000). Although rhamnolipids were initially proposed to play a role in maintaining void spaces between microcolonies or for biofilm dispersal in vitro, we have subsequently shown that PMNs are unable to eradicate bacterial cells within P. aeruginosa biofilms in vitro (Bjarnsholt et al., 2005). This is associated with a QS-regulated phenotype, most notably with the production of rhamnolipid 2 (Jensen et al., 2007) and we have recently suggested that rhamnolipid 2 forms a protective biofilm shield against incoming PMN neutrophils in vivo (Jensen et al., 2007). This model is corroborated by recent data showing that a rhlA mutant is more easily cleared from a pulmonary infections (M. V. Gennip and others, unpublished). In contrast, rhlA/B appear to play no role during MK infection (Zhu et al., 2004).
Immune effects of QS signals and regulated virulence factors
3O-C12-HSL appears to induce apoptosis in neutrophils and macrophages, highlighting that this signal may have dual roles as a global regulator of gene expression in P. aeruginosa and as a virulence factor, directed at the host immune system. It is particularly interesting to note that 3O-C12-HSL, but not HSL signals with shorter side chains such as C4-HSL, acts as a chemoattractant for PMNs (Zimmermann et al., 2006). The selective advantage of luring the PMNs to the infection site and their subsequent killing is not clear, but it is possible that the lysed PMNs are used as a nutrient source or that their release of oxidative radicals or degradative enzymes might cause local tissue damage which could aid in the subsequent dissemination of P. aeruginosa. This possibility is supported by the observation that infected CF patients have been reported to have elevated levels of H2O2 in their breath, which has been linked to high levels of oxidative burst due to cell-mediated defences (Jobsis et al., 2000). Thus it is clear that a significant component of this aggressive pathogen's arsenal of virulence factors is directed at the host immune response. In this regard, effects on the host defence systems may be the dominant mechanism behind its ability to persist.
Thus, the normally well-prepared host is subverted by the invader, and either the host's defensive protocols are manipulated in favour of the pathogen, by modifying the Th1-Th2 response, or the immune response may be blocked by degradation of antibodies (elastase) or the killing of PMNs (rhamnolipid), or the cells within the biofilm may simply not be accessible to immune attack. In this respect, it has been suggested that most of the damage to the lung is due to the host's frustrated immune system attack on the biofilm and not virulence factor production per se (Hoiby et al., 2001). This may be particularly relevant to both eye and lung infections, where 3O-C12-HSL has been shown to attract PMNs. Both infections are characterized by marked infiltration of PMNs, and these have been linked to localized tissue destruction.
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QS inhibition for infection control |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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have shown in vitro that enzymes which degrade AHLs can reduce biofilm and virulence factor production, but this also remains to be demonstrated in vivo (Wang et al., 2007). It is of interest to note that antibodies directed at AHLs can provide some protection in vivo (Miyairi et al., 2006). And while at least part of that effect was attributed to a reduction in 3O-C12-HSL-mediated apoptosis of neutrophils, such antibodies may also mediate a protective effect by preventing the more general changes to the host immune response (described above) or by silencing the QS response. A strategy that uses QS antagonists to block the native signal from interacting with the receptor has also been shown in vitro to control biofilm development (Hentzer et al., 2002), to inhibit virulence factor expression (Hentzer et al., 2002; Rasmussen et al., 2005), to reduce biofilm toxicity and remove the protective shield to PMNs (Bjarnsholt et al., 2005) and to make the biofilm more sensitive to antibiotic treatment (Bjarnsholt et al., 2005; Hentzer et al., 2003). Furthermore, this strategy has been shown to work in animal models of lung infections, demonstrating the utility of targeting the QS system to control these chronic infections (Bjarnsholt et al., 2005; Hentzer et al., 2003; Wu et al., 2001, 2004). |
Concluding remarks |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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). For example, alkaline protease, elastase and exoenzyme S are virulence factors that play roles in the infection of both eyes and lungs. In contrast, while there is strong evidence that rhamnolipids and pyocyanin play roles in chronic lung infection, there is no similar evidence that they play roles during infection of the eye. Loss of las and/or rhl QS genes renders P. aeruginosa strains non-infective in the eye, yet when it occurs after initial infection of the lung, appears to allow a state of chronic infection to occur. QS mutants are rarely isolated from MK, whilst lasR and rhlR mutants are commonly isolated from the lungs of infected patients. This may reflect different strategies for infection in the two diseases, where MK is favoured by an acute, aggressive infection, whilst chronic lung infections are geared for persistence and hence are characterized by lower expression levels of virulence factors and an increased dependence on biofilm formation and maintenance. Single mutations in signal synthase genes leads to reduced virulence in animal models, while at least for the eye, both signal receptors must be lost to affect virulence. Chronic lung isolates are commonly lasR mutants. Thus it is possible that the receptors are required for initial infection, but are dispensable for long-term infection. Immune modulation makes a significant contribution to infection (Fig. 3), where P. aeruginosa, via the secreted HSL signal, can alter the host response to favour an inflammatory response. In addition, much of the damage to the host appears to be the result of an inflammatory response. It will be intriguing to further evaluate the role of QS in these infection types to elucidate how QS manifests itself to result in these distinct infections. One possibility may be related to the role of accessory regulators, noted above, that modulate the QS response. Thus, tissue-specific cues, such as local nutrients or oxygen levels, may play important roles in QS modulation. Despite the differences noted, it is likely that ways of controlling QS would be effective in controlling/treating both types of infections. There have been several suggestions for achieving QS control as a therapeutic. For example, it has been proposed to remove the signal, either through the application of AHL-degrading enzymes, acylases or lactonases (Dong et al., 2001; Xu et al., 2003), or by using monoclonal antibiotics to bind to and sequester the signal (Smith & Iglewski, 2003). Alternatively, it may be possible to develop inhibitors that block the signal–receptor interaction and in this way, control the QS response (Rice et al., 2005; Smith et al., 2003). There may yet be many more unidentified strategies for controlling the QS response with a view to controlling infections that are QS dependent.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTIntroductionQS as a global...The role of QS...QS in chronic lung...QS inhibition for infection...Concluding remarksREFERENCES |
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