Download Cell–cell signalling in bacteria: not simply a matter of quorum

MINIREVIEW
Cell^cell signalling in bacteria: not simply a matter of quorum
Mickaël Boyer1,2,3 & Florence Wisniewski-Dyé1,2,3
1
Université de Lyon, Lyon, France; 2Université Lyon 1, Villeurbanne, France; and 3CNRS, UMR 5557, Ecologie Microbienne, Villeurbanne, France
Correspondence: Florence Wisniewski-Dyé,
CNRS, UMR 5557, Ecologie Microbienne,
Université Lyon 1, 43 boulevard du 11
Novembre 1918, 69622 Villeurbanne Cedex,
France. Tel.: 133 472 44 58 89; fax: 133 426
23 44 68; e-mail:
[email protected]
Present address: Mickaël Boyer, URMITE,
CNRS 6236 – IRD 3R198, Faculté de
Médecine, Université de la Méditerranée, 27
Boulevard Jean Moulin, 13385 Marseille
Cedex 5, France.
Received 25 February 2009; revised 18 June
2009; accepted 29 June 2009.
Final version published online 18 August 2009.
MICROBIOLOGY ECOLOGY
DOI:10.1111/j.1574-6941.2009.00745.x
Abstract
Bacterial signalling known as quorum sensing (QS) relies on the synthesis of
autoinducing signals throughout growth; when a threshold concentration is
reached, these signals interact with a transcriptional regulator, allowing the
expression of specific genes at a high cell density. One of the most studied
intraspecies signalling is based on the use of N-acyl-homoserine lactones (AHL).
Many factors other than cell density were shown to affect AHL accumulation and
interfere with the QS signalling process. At the cellular level, the genetic
determinants of QS are integrated in a complex regulatory network, including QS
cascades and various transcriptional and post-transcriptional regulators that affect
the synthesis of the AHL signal. In complex environments where bacteria exist,
AHL do not accumulate at a constant rate; the diffusion and perception of the AHL
signal outside bacterial cells can be compromised by abiotic environmental factors,
by members of the bacterial community such as AHL-degrading bacteria and also
by compounds produced by eukaryotes acting as an AHL mimic or inhibitor. This
review aims to present all factors interfering with the AHL-mediated signalling
process, at the levels of signal production, diffusion and perception.
Editor: Ian Head
Keywords
degradation; interference; N-acyl-homoserine
lactone; quorum quenching; quorum sensing;
regulation.
Introduction
Bacterial populations can act co-operatively and do so by
emitting and detecting small diffusing compounds, whose
concentration is crucial for a coordinated behaviour. This
process, known as quorum sensing (QS), allows a bacterial
population to evaluate its size and to express specific genes
at a high cell density, i.e. when a ‘quorum’ is reached (Fuqua
et al., 1994). As the size of the bacterial population increases,
so does the concentration of the autoinducing signal, which
diffuses in and out of bacterial cells. Once a threshold
concentration of the signal is reached, the compound is
detected and triggers the activation or the repression of
target genes. Some of the most-studied bacterial autoinducers are N-acyl-homoserine lactones (AHL) synthesized by
LuxI-type proteins and these have been reported so far in
over 70 genera belonging to the Proteobacteria; AHL interact
FEMS Microbiol Ecol 70 (2009) 1–19
with LuxR regulators and are used to regulate multiple
functions, such as bioluminescence, synthesis of virulence
factors, synthesis of antimicrobial compounds, production of
exopolysaccharides, motility, biofilm development, etc. QScontrolled processes are often crucial for successful bacteria–
host interactions, whether symbiotic or pathogenic.
The concept of AHL-mediated bacterial communication
was initially based on studies carried out on clonal populations under laboratory conditions; however, natural bacterial populations live in complex environments where
biodiversity and abiotic parameters are constantly fluctuating. Thus, the signalling process is directly influenced by
abiotic factors (such as pH, temperature and medium
composition) and biotic factors (such as other members of
the bacterial community) that can modulate signal genesis,
diffusion, interception and degradation and that can produce parasitic signals.
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
2
Many studies have also demonstrated that QS is a far
more complex regulatory process than initially described, as
luxI and luxR genes are regulated, directly or indirectly, by a
number of transcriptional and post-transcriptional regulators responding to environmental conditions. Thus, QS is
integrated in a global regulatory network in order to control
AHL production according to various factors (such as
trophic conditions) and to optimize the expression of QSregulated genes.
This review aims to expose the different levels of regulation involved in AHL production inside the bacterial cell
and the numerous environmental factors, whether abiotic or
biotic, which can affect the fate of AHL outside the bacterial
cell or interfere with signal perception.
Regulation of the synthesis and
accumulation of AHL signals within
bacterial cells
Genetic determinants of QS and QS cascade
Most of the AHL synthases described so far belong to the
LuxI family, so called after the identification of the Vibrio
fischeri AHL synthase that regulates bioluminescence. LuxItype proteins direct the formation of an amide bond between
S-adenosylmethionine and the acyl moiety of the cognate acyl
carrier protein (ACP) (Hanzelka & Greenberg, 1996; Moré
et al., 1996). Site-directed mutagenesis on LuxI of V. fisheri
and RhlI of Pseudomonas aeruginosa revealed critical conserved amino acids for the synthase activity in the N-terminal
part; the less conserved C-terminal part is involved in the
recognition of acyl chains carried by ACP (Hanzelka et al.,
1997). The nature of available substrates (amount of ACPs
available in the cell), the specificity of AHL synthases for the
different ACPs and the presence of several AHL synthases
govern the nature of AHLs synthesized by a particular
bacterium and the kinetics of AHL production. The majority
of AHL synthases can accept several acyl-ACPs, leading to the
synthesis of a set of different AHLs, as demonstrated for YtbI
of Yersinia pseudotuberculosis, which can synthesize up to 24
different AHLs (Ortori et al., 2007).
AHL perception is mediated by a transcriptional regulator
of the LuxR family, referring to the protein regulating the
bioluminescence process initially evidenced in V. fisheri.
Despite their low similarity, LuxR homologues all possess
several conserved amino acids (Whitehead et al., 2001) and
an identical architecture: an N-terminal moiety involved in
interaction with the AHL signal, a C-terminal moiety with a
helix-turn-helix motif involved in interaction with DNA, the
central part of the protein allowing oligomerization (Stevens
& Greenberg, 1997; Zhu & Winans, 1999; Fuqua & Greenberg, 2002). A few LuxR homologues, such as EsaR of Pantoea
stewartii, function as repressors as they can bind DNA in the
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
M. Boyer & F. Wisniewski-Dyé
absence of AHLs, impeding the transcription of target genes;
AHL binding reduces EsaR affinity for DNA, relieving the
repression (von Bodman et al., 1998; Minogue et al., 2002).
In various bacteria, luxI homologues belong to the QS
regulon; this creates a positive feedback loop that amplifies
AHL synthesis, allowing an efficient coordination of regulation at the population level (Choi & Greenberg, 1991; Fuqua
& Winans, 1994; Seed et al., 1995). Conversely, antiactivators such as TraM and TrlR of Agrobacterium tumefaciens,
which interact with the TraR regulator, or QscR of
P. aeruginosa, which can compete with LasR for AHL
binding, can impede the premature expression of target
genes at a low cell density and delay the establishment of the
positive feedback loop (Fig. 1) (Luo et al., 2000; Chai et al.,
2001; Lequette et al., 2006).
Several bacteria possess several luxR/luxI systems (Table 1)
that are often organized in hierarchical networks. In the
opportunistic pathogen P. aeruginosa, well known for its
devastating effects on cystic fibrosis patients, QS is essential
for chronic infection as it controls adhesion, biofilm formation
and expression of virulence factors. The QS network consists of
two LuxI/LuxR circuits arranged in series: LasI/LasR/3oxo,C12HSL and RhlI/RhlR/C4-HSL. The LasR/3oxo,C12-HSL complex activates a variety of target genes involved in virulence and
also exerts a transcriptional control of rhlR and rhlI (Latifi
et al., 1996); thus, induction of the genes under control of the
rhl system occurs subsequent to the induction of genes under
control of the las system. Transcriptome analyses of P. aeruginosa revealed three classes of QS-regulated genes that are
expressed at different times over growth: genes that respond
to only one AHL, genes that respond to either AHL and genes
that require both AHLs to be activated (Schuster et al., 2003;
Wagner et al., 2003; Wagner et al., 2004). The hierarchical
network of QS systems allows a chronologically ordered
sequence of gene expression that might be decisive for a
successful infection (Schuster et al., 2003).
In the mammalian enteropathogen Y. pseudotuberculosis
that causes gastroenteritis in humans and chronic infections
in immunocompromised patients, two QS systems, the YpsR/
YpsI and YtbR/YtbI, modulate swimming motility via regulation of flhCD and fliA; flhCD and fliA encode, respectively,
the motility master regulator and the flagellar sigma factor
and fliA expression is flhCD dependent (Atkinson et al., 1999,
2008). The YpsR/YpsI system exerts a hierarchical positive
regulation on the YtbR/YtbI and the AHLs synthesized via
YtbI play a dual role, activating flhDC, but repressing fliA.
Yersinia pseudotuberculosis is motile at 22 1C, but not at 37 1C,
and QS is thought to prevent motility by repressing fliA, thus
allowing FlhCD to control other genes unrelated to the
flagellar cascade, but required for invasion of a mammalian
host at 37 1C (Atkinson et al., 2008).
Rhizobium leguminosarum bv. viciae, a soil bacterium that
can nodulate pea, vetch and lentil, possesses four QS systems,
FEMS Microbiol Ecol 70 (2009) 1–19
Cell–cell signalling in bacteria
3
Fig. 1. Regulation of the synthesis and accumulation of AHL signals within bacterial cells. To depict a global picture, all the different systems have been
artificially gathered in a single bacterial cell. Thick arrows indicate AHL fluxes; thin arrows indicate regulation processes and AHL synthesis. Dashed
arrows correspond to transcription and translation. AHL synthesis per se is depicted in orange. The following levels of transcriptional regulation are
depicted in blue: effect of environmental cues (such as medium composition or temperature), effect of physiological factors (such as growth phase),
activation by a dimer of LuxR-type regulators, formation of complexes of LuxR with an antiactivator (such as TraM). Post-transcriptional regulation is
illustrated (in green) with sRNAs that sequester RNA-binding proteins (such as RsmA); when sRNAs are not transcribed, RNA-binding proteins interact
with luxI-type mRNA, triggering its degradation. Factors affecting directly AHL synthesis or accumulation within the cell are depicted in yellow; these are
precursors’ availability, degradation by endogenous lactonase or acylase, sequestration by orphan LuxR-type regulators (such as QscR), diffusion or
active transport. For clarity, the occurrence of a QS cascade and regulation by other signalling molecules have not been represented on this figure.
with each synthase being able to make a specific set of AHLs,
and an additional orphan regulator (Table 1) (WisniewskiDyé & Downie, 2002; Sanchez-Contreras et al., 2007). The
cinR/cinI/3OH,C14:1-HSL system, at the top of a regulatory
cascade, regulates all other QS loci (Lithgow et al., 2000) and
appears to act as an overall switch potentially influencing
many aspects of rhizobial physiology, such as survival,
transfer of symbiotic plasmid and association with specific
legumes (Wisniewski-Dyé & Downie, 2002).
Transcriptional and post-transcriptional
regulation
AHL synthesis can be modulated independently of cell
density by various physiological factors (such as trophic
FEMS Microbiol Ecol 70 (2009) 1–19
conditions) through two-component regulatory systems,
transcriptional regulators and post-transcriptional control.
One of the earliest examples came from V. fischeri, the AHL
synthesis of which is activated by the catabolic repressor
CRP in response to specific substrates (Dunlap & Greenberg, 1985; Dunlap, 1989). One of the most-studied twocomponent systems is the GacS/GacA system, highly conserved in Pseudomonas species, which is interconnected with
the Rsm (repressor of secondary metabolites) system allowing post-transcriptional control of QS (for a review, see
Bejerano-Sagie & Xavier, 2007). The Rsm system involves
RsmA, a protein able to complex with mRNAs to trigger
their degradation by RNAses, and small noncoding RNAs
(sRNAs). These sRNAs regulate gene expression either by
binding to mRNA, affecting their stability or their
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
4
M. Boyer & F. Wisniewski-Dyé
Table 1. Bacteria-containing multiple QS systems
Species/strain
QS signal
LuxI/LuxR
homologues
QS-regulated
phenotypes
Burkholderia cenocepacia
K56-2
C6-HSL; C8-HSL
C6-HSL; C8-HSL
CciI/CciR
CepI/CepR
Virulence factors
Virulence factors
Burkholderia pseudomallei
1026b
C8-HSL; C10-HSL; 3OH,C8-HSL;
3OH,C10-HSL; 3oxo,C14-HSL
C8-HSL; C10-HSL; 3OH,C8-HSL;
3OH,C10-HSL; 3oxo,C14-HSL
C8-HSL; C10-HSL; 3OH,C8-HSL;
3OH,C10-HSL
C6HSL
C8-HSL; C10-HSL; C12-HSL;
3oxo,C10-HSL
3oxo,C6-HSL
BpmI2/BpmR2
Virulence, exoprotease
Malott et al. (2005)
Huber et al. (2001), Lewenza
& Sokol (2001), Lewenza et al.
(1999, 2002)
Ulrich et al. (2004)
BpmI3/BpmR3
Virulence, exoprotease
Ulrich et al. (2004)
PmlI1/PmlR1
Virulence, exoprotease
Burkholderia vietnamiensis
G4
Erwinia carotovora ssp.
carotovora ATCC 39048
Pseudomonas chlororaphis
(aureofaciens) 30–84
Pseudomonas aeruginosa
PAO1
Rhizobium etli CNPAF512
Rhizobium leguminosarum
bv. viciae 8401pRL1JI
Sinorhizobium meliloti
Rm1021
Yersinia pestis KIM61
Yersinia pseudotuberculosis
III
CepI/CepR
BviI/BviR
CarI/CarR
C6HSL
VirR
PhzI/PhzR
uncharacterized
3oxo,C12-HSL
CsaI/CsaR
LasI/LasR
C4-HSL
Short-chain HSLs
3-Hydroxy-(saturated long chain)HSL
3OH,C14:1-HSL
C6-HSL; C7-HSL; C8-HSL; 3OH,
C8-HSL
C8-HSL; 3oxo,C8-HSL; 3oxo,
C10-HSL
C6-HSL; C7-HSL; C8-HSL
RhlI/RhlR
RaiI/RaiR
CinI/CinR
C8-HSL; C12-HSL; 3oxo,C14-HSL;
C16:1-HSL; 3oxo,C16:1-HSL;
3oxo,C16-HSL; C18-HSL
3oxo,C6-HSL; 3oxo,C8-HSL
3oxo,C6-HSL; 3oxo,C8-HSL
3oxo,C6-HSL; C6-HSL
C6-HSL; C8-HSL
References
Ulrich et al. (2004), Valade
et al. (2004)
Unknown
Conway & Greenberg (2002)
Unknown
Conway & Greenberg (2002),
Malott & Sokol (2007)
Exoenzymes, virulence factors, Jones et al. (1993), McGowan
carbapenem
et al. (1995, 2005), Burr et al.
(2006)
Phenazine, biofilm formation
Proteases, surface properties
Extracellular enzymes, biofilm
formation, RpoS,
rhamnolipids
CinI/CinR
RaiI/RaiR
Nodulation, growth inhibition
Nitrogen fixation, nodulation,
growth inhibition
Growth inhibition
Unknown
TraI/TraR
Plasmid transfer
RhiI/RhiR
ExpR
SinI/SinR
Nodulation efficiency
EPS integrity
EPSII production, swarming
ExpR
EPSII production, swarming
Mel (putative)
YspI/YspR
YpeI/YpeR
YpsI/YpsR
YtbI/YtbR
Unknown
Unknown
Unknown
Cell aggregation and motility
Cell aggregation and motility
Pierson et al. (1994), Maddula
et al. (2006), Zhang & Pierson
(2001), Maddula et al. (2006)
Pearson et al. (1997)
Latifi et al. (1995, 1996)
Rosemeyer et al. (1998)
Daniels et al. (2002)
Lithgow et al. (2000)
Wisniewski-Dyé et al. (2002)
Wilkinson et al. (2002),
Danino et al. (2003)
Rodelas et al. (1999)
Edwards et al. (2009)
Marketon & Gonzalez (2002),
Marketon et al. (2003),
Teplitski et al. (2003), Gao
et al. (2005)
Pellock et al. (2002), Gao et al.
(2005)
Marketon et al. (2002)
Kirwan et al. (2006)
Kirwan et al. (2006)
Atkinson et al. (1999, 2008)
Atkinson et al. (1999)
Bacteria-containing cross-regulated QS systems.
EPS, exopolysaccharides.
translation, or by binding to regulatory proteins (such as
RsmA) impeding their activity (Fig. 1). The use of sRNAs
with a high turnover, rather than proteins, certainly allows
the cells a swifter response.
In the opportunistic pathogen P. aeruginosa, inactivation
of the GacA regulator was initially shown to reduce the
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
synthesis of C4-HSL, and of the two LuxR-type transcriptional regulators, RhlR and LasR, and consequently to affect
C4-HSL/RhlR-regulated functions (production of pyocyanin,
cyanide and lipase) (Reimmann et al., 1997). GacA activates
the expression of numerous genes, including rsmZ- and
rsmY-encoding sRNAs (Kay et al., 2006). RsmA, whose
FEMS Microbiol Ecol 70 (2009) 1–19
5
Cell–cell signalling in bacteria
synthesis is dependent on cell density, can activate rsmZ and
rsmY expression; both RsmZ and RsmY can sequester RsmA,
hindering its activity and thus creating a negative feedback
loop. Thus, activation by the GacS/GacA triggers inactivation
of RsmA via the sRNAs RsmZ and RsmY. In the absence
of GacS/GacA activation, RsmA can interact with rhlI
transcripts, inhibiting their translation and hence limiting
C4-HSL synthesis (Pessi et al., 2001).
A second two-component regulatory system, the PprA/
PprB, which controls membrane permeability and antibiotic
sensitivity in P. aeruginosa, is also interconnected with QS;
an insertion mutation in pprB (encoding the response
regulator) causes a drastic reduction in lasI, rhlI and rhlR
expression, and consequently a reduction in virulence factor
production and cell motility (Dong et al., 2005). Furthermore, the 3oxo,C12-HSL influx is significantly reduced in
the pprB mutant, hindering the establishment of the positive
feedback loop of lasI and hence the expression of rhlI/rhlR
that is partially under the control of the lasI/lasR/3oxo,C12HSL (Dong et al., 2005). However, signals recognized by the
cognate sensor proteins (GacA and PprA) remain to be
characterized. RetS, an unusual hybrid sensor kinaseresponse regulator of P. aeruginosa, in concert with the GacS/
GacA system and the LadS regulator, controls the expression
of virulence factors (such as the type III secretion system) and
is required for acute and chronic infection (Laskowski &
Kazmierczak, 2006; Ventre et al., 2006).
A multitude of other transcriptional regulators have
been shown to interact with the P. aeruginosa QS network
(for a review, see Schuster & Greenberg, 2006). The regulation of QS genes is indeed under the control of the alarmone
cAMP (via the Crp homologue, Vfr) (Albus et al., 1997;
Beatson et al., 2002), amino acid starvation (via the
stress response protein RelA) (van Delden et al., 2001;
Erickson et al., 2004), oxygen-limiting conditions (via the
anaerobic regulator ANR) (Pessi & Haas, 2000) and oxidative stress and the presence of human serum (Juhas et al.,
2004).
The interconnection of regulators with QS networks was
also reported in other Pseudomonas species. The GacS/GacA
system controls the production of AHL required for the
production of phenazines, antimicrobial compounds mediating the biocontrol activity of Pseudomonas aureofaciens
30–84 against fungal phytopathogens (Chancey et al., 1999);
in Pseudomonas chlororaphis PCL1391, this regulation also
involves PsrA (Pseudomonas sigma regulator), which
positively regulates phzI/phzR expression via RpoS (Girard
et al., 2006). GacA and PsrA act as master regulators of
the virulence of plant-pathogenic Pseudomonas syringae
pv. tomato, notably by controlling the expression of transcriptional activators (including LuxR regulators), alternate
sigma factors (such as RpoS) and regulatory RNA (rsmB and
rsmZ, for GacA) (Chatterjee et al., 2003, 2007).
FEMS Microbiol Ecol 70 (2009) 1–19
In the plant-pathogen Erwinia carotovora ssp. carotovora,
the GacS/GacA system regulates the synthesis of a unique
sRNA, RsmB, which can bind to RsmA and inhibit its
activity. RsmB is repressed by multiple components such as
KdgR (a transcriptional regulator activated by plant signals)
and HexA (a global regulator). In the absence of AHLs (i.e.
at a low cell density), the AHL receptors, ExpR1 and ExpR2,
activate the synthesis of RsmA by binding the rsmA promoter; this activation is inhibited in the presence of AHLs.
Thus, at a high cell density (i.e. when the GacS–GacA twocomponent system is activated), the expression of QSregulated phenotypes is no longer inhibited by RsmA (for a
review, see Barnard & Salmond, 2007).
QS can also be regulated at the level of protein stability;
the ATP-dependent Lon protease acts as a negative regulator of AHL production in Pseudomonas putida and
P. aeruginosa, notably by degrading LasI and hence repressing the expression of lasR/lasI (Bertani et al., 2007; Takaya
et al., 2008). In the absence of its AHL ligand, the LuxR
regulator of A. tumefaciens, TraR, is susceptible to degradation by Clp and Lon proteases, indicating the importance of
these proteases in QS timing and regulation (Zhu & Winans,
2001).
Endogenous AHL-inactivating enzymes
Two families of bacterial enzymes with AHL-degrading
activity have been evidenced: AHL lactonases can hydrolyse
the ester bond of the lactone ring, and AHL acylases can
hydrolyse the amide bond of the molecule, releasing the
homoserine lactone moiety and the corresponding fatty
acid. Initially, such enzymes were identified, respectively, in
Bacillus sp. and Variovorax paradoxus, bacteria that do not
synthesize AHL signals (see Biotic factors intrinsic to the
bacterial population) (Dong et al., 2000; Leadbetter &
Greenberg, 2000). More recently, these enzymatic activities
were found in AHL-producing bacteria belonging to the
genera Agrobacterium and Pseudomonas.
In A. tumefaciens, attM encodes an AHL lactonase able to
inactivate the TraI-made signal, 3oxo,C8-HSL. During the
exponential phase, attM expression is repressed by the AttJ
regulator, allowing 3oxo,C8-HSL accumulation and expression of the QS-regulated phenotype, i.e. conjugative transfer
of the Ti plasmid (pTi). When cells enter the stationary
phase, the inhibition of plasmid transfer is observed and
coincides with a decrease in the AHL concentration due to
AttM expression (Zhang et al., 2002). Under these conditions of starvation, AHL inactivation would save the energetic cost necessary for the QS-regulated conjugation.
Moreover, attM expression is activated by g-amino butyric
acid (GABA), a compound synthesized by numerous organisms including plants (Chevrot et al., 2006). As GABA
synthesis increases when the plant is wounded, it could
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
6
stimulate AHL inactivation by AttM in A. tumefaciens cells
located in the vicinity of the wound and modulate pTi
transfer, and consequently affect bacterial virulence. However, a recent study showed that induction of attM resulted
in only a twofold decrease in intracellular AHL levels, and
mating experiments performed in developing tumours
showed that AttM had no significant effect on plasmid
transfer (Khan & Farrand, 2009). Two other enzymes
homologous to AHL lactonases, AiiB and AiiC, are encoded
by the A. tumefaciens genome, but AHL-degrading activity
was evidenced only for AiiB (Carlier et al., 2003).
AHL-acylase and AHL-lactonase activities have been
identified in numerous soil isolates belonging to the genus
Pseudomonas, notably P. aeruginosa and P. syringae (Huang
et al., 2003; Huang et al., 2006; Shepherd & Lindow, 2009).
The PvdQ enzyme, homologous to AHL acylases, inactivates
long acyl chain AHLs more efficiently than short acyl chain
AHLs, and consequently its overexpression prevents
3oxo,C12-HSL accumulation. However, inactivation of pvdQ
does not abolish the ability of P. aeruginosa to grow on a
medium containing AHL as the sole carbon source, suggesting the existence of other AHL-degrading enzymes (Huang
et al., 2003). The QuiP protein, displaying 21% homology
with PvdQ, is also an AHL acylase that specifically degrades
long acyl chain AHLs in P. aeruginosa; however, its role and
its expression pattern remain to be determined (Huang
et al., 2006). These AHL acylases would modulate the
proportion of the two AHLs synthesized, in order to finetune their corresponding target genes.
Even if these endogenous enzymes can accelerate AHLs
turnover and degradation, their activity is not solely dedicated to AHL inactivation as they can be involved in other
metabolic pathways. In A. tumefaciens, attM belongs to the
attKLM operon-encoding enzymes involved in an assimilative pathway of g-butyrolactone; transcription of the
attKLM operon is activated by g-butyrolactone and also by
GABA (Carlier et al., 2004). As for pvdQ of P. aeruginosa,
this gene is also involved in the biosynthesis of the siderophore pyoverdine (Ochsner et al., 2002; Lamont & Martin, 2003).
AHL diffusion and transport through membrane
AHLs, which are amphipathic molecules, are expected to
freely diffuse from the inside to the outside, and vice versa,
but this has been demonstrated only for the short acyl chain
AHL 3oxo,C6-HSL using a 3H-labelled derivative (Kaplan &
Greenberg, 1985). As the hydrophobicity is affected by the
length of the acyl chain, the number of insaturations and the
nature of the C3 substituent (H, O or OH), the diffusion
speed is correlated with the nature of the acyl chain and long
acyl chain AHLs, if they can diffuse at all, would diffuse
more slowly than short acyl chain AHLs.
c 2009 Federation of European Microbiological Societies
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M. Boyer & F. Wisniewski-Dyé
In P. aeruginosa, an active efflux of 3oxo,C12-HSL was
evidenced, whereas C4-HSL freely diffuse across the cell
membrane (Pearson et al., 1999). This efflux is mediated by
a multidrug-efflux pump, encoded by the mexAB-oprM
operon; a defined mutant lacking this pump accumulates
3oxo,C12-HSL with a higher concentration in the cytoplasm
than in the extracellular medium. A second efflux pump,
encoded by the mexGHI-opmD operon, is linked to QS;
P. aeruginosa mutants no longer expressing this pump
exhibit a reduced production of AHLs in the extracellular
medium and reduced production of virulence factors
(Aendekerk et al., 2002). Burkholderia pseudomallei KHW
can produce six different AHLs and these molecules trigger
transcription of the bpeAB-oprB genes coding for an activeefflux pump required for the extracellular secretion of all
AHLs; AHL production is undetectable in a bpeAB-null
mutant and its virulence is attenuated (Chan & Chua,
2005; Chan et al., 2007). This suggests the possibility of
attenuating B. pseudomallei virulence using inhibitors of the
BpeAB-OprB efflux pump.
So far, active efflux of AHLs has only been evidenced in
P. aeruginosa and in B. pseudomallei; as a significant number
of bacteria were shown to produce long acyl chain AHLs, it
is likely that efflux systems are used by other bacteria. Via
this type of transporter, the different AHLs produced by a
bacterium can accumulate differentially inside and outside
the cell; thus, the threshold concentration necessary to
trigger QS-regulated genes will rely on cell number but also
on the nature of the synthesized AHL. To our knowledge, no
system involved in the entry of AHLs into the cytoplasm has
been evidenced.
Regulation of AHL production by other
endogenous signals
Gram-negative bacteria can produce signalling molecules
other than AHLs. As a single bacterium can synthesize
several types of signals, the synthesis of AHLs can be
regulated by the production and perception of the other
signals. For example, P. aeruginosa produces 2-heptyl-3hydroxy-4-quinolones, collectively named PQS (Pseudomonas quinolone signal), whose synthesis is observed after the
exponential phase of growth and relies on LasR/3oxo,C12HSL (Pesci et al., 1999). The exogenous addition of PQS
activates the expression of rhlI, the gene involved in C4-HSL
synthesis, and consequently the expression of Rhl-regulated
genes during the stationary phase. In return, C4-HSL would
regulate negatively the production of PQS, but whether this
control is direct or indirect remains to be demonstrated
(McGrath et al., 2004; Wade et al., 2005). This complex
regulatory network, relying on both AHLs and PQS, plays a
central role in coordinating virulence, antibiotic resistance
and fitness in P. aeruginosa.
FEMS Microbiol Ecol 70 (2009) 1–19
7
Cell–cell signalling in bacteria
In addition to AHLs and PQS, P. aeruginosa produces
cyclic dipeptides (diketopiperazines) that could act as signalling molecules (Holden et al., 1999). These compounds
could interfere with the signalling process, by competing
with the AHL for binding to LuxR regulators. In this way,
diketopiperazine could inhibit the feedback loop of lasI and
rhlI and affect the accumulation of AHLs.
In the plant-pathogen Ralstonia solanacearum, cell–cell
communication is integrated in a complex regulatory network, allowing the induction of virulence genes in response
to plant signals and nutritional starvation. Ralstonia solanacearum synthesizes 3-hydroxypalmitic acid (3-OH-PAME)
accumulating throughout bacterial growth (Flavier et al.,
1997a). At a high cell density, 3-OH-PAME allows the
expression of the transcriptional regulator PhcA, which
induces the expression of virulence factors and the synthesis
of AHLs (Flavier et al., 1997b). However, the QS regulon
remains to be characterized, as well as the involvement of QS
in virulence.
Furanosyl borate diesters, also named AI-2, are signalling
molecules found in numerous Gram-negative and Grampositive bacteria and are thought to act as interspecies
signals (Waters & Bassler, 2005). In V. fischeri, AI-2 indirectly regulates C8-HSL synthesis and affects luminescence
regulation (Lupp & Ruby, 2004).
Environmental factors affecting the
synthesis, stability, diffusion and
perception of AHLs signals
Abiotic factors
pH and temperature
pH and temperature are environmental factors affecting the
half-life of AHLs. Indeed, alkaline pH and high temperature
(4 37 1C) favour the opening of the lactone ring, producing
an N-acyl-homoserine compound devoid of signalling properties. Whereas 70% of N-propionyl-homoserine lactone
(C3-HSL) is hydrolysed at pH 6, C4-HSL is completely
hydrolysed at pH 8 (Yates et al., 2002; Decho et al., 2009).
Consequently, AHLs must contain an acyl chain with at least
four carbons for sufficient stability and activity under pH
conditions encountered by most bacteria. Moreover, long
acyl chain AHLs (4 C8) are less sensitive to alkaline lysis and
to elevated temperatures than short acyl chain AHLs.
Culture of E. carotovora ssp. carotovora in a rich laboratory medium is accompanied by alkalinization in the
stationary phase. This alkalinization leads to inactivation of
3oxo,C6-HSL and reduced production of carbapenem,
whose synthesis is QS regulated. In a buffered medium,
3oxo,C6-HSL and carbapenem can be detected during the
stationary phase when bacteria are grown at 30 1C (optimal
FEMS Microbiol Ecol 70 (2009) 1–19
growth temperature), but remain at very low concentrations
at 37 1C (Byers et al., 2002; McGowan et al., 2005). Interestingly, one of the plant responses following infection by
E. carotovora is the activation of a proton pump allowing
the alkalinization of the infection zone and hence the
inactivation of AHLs; such a response is likely to interfere
with QS regulation of virulence factors.
The influence of temperature on AHL synthesis was
clearly demonstrated for the psychrotolerant bacterium
Pectobacterium atrosepticum (causing soft rot of potato)
whose pectate lyase production is under QS regulation.
Maximal AHL synthesis is observed at the optimal growth
temperature (24 1C) and is directly correlated with expI
transcripts; at 12–15 1C, AHL production is reduced
whereas pectate lyase production is optimal, suggesting a
thermoregulation occurring downstream quorum signalling
(Latour et al., 2007). The influence of temperature on AHL
synthesis has also been studied in the food-borne human
opportunistic pathogen Aeromonas hydrophila that regulates
exoprotease production and biofilm development through
QS; the concentration of C4-HSL is lower at 12 1C than at
22 or 30 1C (the optimal growth temperature) despite
reaching dense populations, indicating that 12 1C is not
inhibitory to C4-HSL production and that quorum signalling might occur under real food conditions (MedinaMartinez et al., 2006).
Medium composition
In E. carotovora ssp. carotovora, the nature of the carbon
source (and also the temperature of growth) influences
carbepenem production by modulating the level of carI
transcription; the concentration of 3oxo,C6-HSL is high,
intermediate or low in, respectively, a sucrose, a glucose or a
glycerol-grown culture (McGowan et al., 2005). In
A. hydrophila, C4-HSL synthesis occurs in Luria–Bertani
broth supplemented with 0.1% and 0.5% glucose whereas
no synthesis is detected in 1% glucose (Medina-Martinez
et al., 2006); the QS regulation of exoproteases would allow
this bacterium to use alternative carbon sources when the
medium becomes deficient in glucose. In R. leguminosarum,
where QS notably regulates transfer of a symbiotic plasmid,
the quantity and the ratio of each AHL are also affected by
the composition of the growth medium (Lithgow et al.,
2001). Molecular mechanisms underlying the finely tuned
production of AHLs according to the carbon source available remain unknown.
By studying the expression of the las and rhl systems of
P. aeruginosa in different media differing in nutrient composition and oxygen composition, the expression of
both systems appears to be significantly affected by nutritional growth conditions (Wagner et al., 2003; Duan &
Surette, 2007). A differential regulation of lasI and rhlI is
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
8
observed when bacteria are cultivated anaerobically (but not
aerobically) in rich media: the transcription level of lasI is
higher whereas rhlI transcription is repressed (Wagner et al.,
2003). The expression level of AHL synthases (LasI and
RhlI) is not always correlated with the expression level of the
corresponding regulatory proteins (LasR and RhlR), suggesting that those genes are independently regulated, allowing fine-tuning of each system (Duan & Surette, 2007).
LuxR-type regulators and their cognate AHL could thus play
different roles according to growth culture conditions.
One of the nutrient deficiencies that can dramatically
affect AHL production, at least in P. aeruginosa, is iron
deficiency. Iron deficiency leads to enhanced formation of
virulence factors and to inhibition of oxygen transfer, which
may decrease the formation of oxidants or increase the
solubility or availability of iron (Kim et al., 2003). The
expression of the las system and markedly of the rhl system
increases in response to iron limitation (Bollinger et al.,
2001; Duan & Surette, 2007). Moreover, a strong correlation
between the exhaustion of iron and lasR expression is
observed under oxygen limitation (Kim et al., 2005). These
findings are highly relevant as iron availability is often
limited in biofilm, the primary mode of growth of this
pathogen in the lung of cystic fibrosis patients, and as host
cell defence mechanisms include iron sequestration and
formation of oxidants.
Mass transfer
Mass transfer processes, such as diffusion and advection, can
strongly influence AHLs accumulation within a given environment. The number of bacterial cells required to reach
the threshold concentration of AHL can thus vary considerably according to the diffusion rate of AHLs. The latter is
dependent on the nature of a given AHL, on medium
hydrophobicity, but can also be affected by bacteria themselves; indeed, several AHL-producing species are also capable of secreting polysaccharides constitutive of biofilm
matrixes (Kolter & Greenberg, 2006). In a P. aeruginosa
biofilm, it was suggested that the presence of hydrophobic
exopolysaccharides in the biofilm matrix would limit the
diffusion of AHL, because the 3oxo,C12-HSL concentration
is higher within the biofilm than on the surface circulating
fluid (Charlton et al., 2000). C4-HSL, being less hydrophobic than 3oxo,C12-HSL, have fewer interactions with the
biofilm matrix and would be mainly responsible for the
signalling process (Singh et al., 2000).
AHLs can also be transported by circulating fluids, a
phenomenon termed advection, a process that will lead to
signal washing and dilution (Horswill et al., 2007). This
physical factor can play an important role at the local scale,
notably when bacteria form biofilms. In P. aeruginosa, the
speed of circulating fluids affects significantly the maturac 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
M. Boyer & F. Wisniewski-Dyé
tion of biofilm, whose structure depends on QS-regulated
functions (Purevdorj et al., 2002). AHL accumulation would
be greater within the biofilm than at the biofilm surface,
leading to premature induction of QS-regulated functions in
cells localized within the biofilm (de Kievit et al., 2001).
The plant-pathogen bacterium P. syringae, in which QS
controls traits involved in virulence and epiphytic fitness,
occurs on leaf surfaces in aggregates of various sizes. AHL
accumulation within these aggregates is favoured on dry
leaves, suggesting the influence of humidity on AHL diffusion outside aggregates (Dulla & Lindow, 2008). Thus, rain
flowing out of leaves can disrupt cell–cell communication of
epiphytic bacteria.
In addition to functioning as sensors of population density,
low-cost autoinducers such as AHLs could be released as a
proxy to determine whether secreted molecules will rapidly
diffuse away from the cell, a phenomenon known as diffusion
sensing (Redfield, 2002; Hense et al., 2007). Diffusion sensing
could allow individual cells to minimize the loss of costly
compounds (such as exoenzymes, siderophores, antibiotics)
by extracellular diffusion.
Biotic factors intrinsic to the bacterial
population
Cell density
The initial function attributed to AHL signals was to
estimate population density. The two factors determining
population density (number of cells and volume available
for growth) can vary independently, the number of cells
increasing within a limited volume or the number of cells
being constant while the volume becomes smaller. AHL
concentration can increase accordingly, and when reaching
a threshold concentration, allow the synchronized expression of specific genes at the population level. In certain
bacteria, this phenomenon is amplified by a positive feedback loop on AHL production.
The expression of specific genes when the population has
reached a ‘quorum’ is often crucial for bacteria–host interactions. Vibrio fischeri is able to colonize the light organ of
the squid Euphrymna scolopes at a very high cell density
(1010 cells mL 1); emission of light by V. fischeri is due to
AHL accumulation in the limited volume of the light organ.
If the light organ was smaller, a lower number of bacterial
cells would be required to induce light, but the intensity of
light would probably be insufficient for the squid to cheat its
predators. A diffusion model showed that levels of bioluminescence are lower in planktonic V. fischeri cells compared
with cells adhered onto glass surfaces; QS can occur locally
in two-dimensional surface samples and is a function of cell
population density as well as signal diffusion time (Parent
et al., 2008).
FEMS Microbiol Ecol 70 (2009) 1–19
9
Cell–cell signalling in bacteria
Spatial distribution of cells
The concept of QS comes from studies undertaken on clonal
populations, mainly from homogenous liquid cultures.
However, these cultural conditions do not reflect natural
fluctuating environmental conditions encountered by
bacterial populations. In complex environments, such as a
rhizosphere, the spatial distribution of cells is far from
homogenous, cells are rather isolated or form clusters and
are localized where diffusion rate and nutrient availability
are temporally changing. A mathematical modelling, using a
definite volume and a constant number of cells and taking
into account the diffusion and production rates of AHLs,
the existence of a positive feedback loop for AHL production and the spatial distribution of cells, shows that the latter
is more important than cell density for sensing: the threshold AHL concentration required to induce QS-regulated
functions is reached only when cells are clustered and when
a positive feedback loop is present (Hense et al., 2007). Thus,
it was suggested that the positive feedback loop acting on
AHL synthesis is dedicated to coordinating more rapidly a
concerted response at the population level, independent of
the spatial distribution of cells.
Biotic factors within the bacterial community
AHL inactivation by bacterial enzymes
In natural environments, microorganisms form communities where AHL-producing bacteria interact with other
organisms that are able to degrade AHLs. Processes interfering with cell–cell communication are known as quorum
quenching. AHL-degrading enzymes fall into two categories:
AHL-lactonases (AiiA family) and AHL-acylases/amidohydrolases (AiiD family) (Dong et al., 2000; Leadbetter &
Greenberg, 2000; Zhang et al., 2002; Lin et al., 2003;
Park et al., 2005). These enzymes have been identified in a
huge number of bacterial isolates, notably soil isolates
(Reimmann et al., 2002; Zhang, 2003). AHL lactonases, the
most-studied AHL-degrading enzymes, were first identified
in several Bacillus species (Dong et al., 2002; Lee et al., 2002).
AHL lactonases were also evidenced in Klebsiella pneumoniae
(ahlK), in the AHL producer A. tumefaciens (AttM and AiiB)
and in Gram-positive bacteria such as Arthrobacter (AhlD)
and Rhodococcus erythropolis (QsdA that does not display
homology to AiiA) (Park et al., 2003; Uroz et al., 2008).
Bioinformatic studies revealed that genes homologous to
aiiA are present in other Rhizobiaceae such as Bradyrhizobium japonicum or Mesorhizobium loti (Carlier et al., 2003).
Two metagenomic approaches identified new genes encoding
lactonases displaying low similarity to previously characterized lactonases (Riaz et al., 2008; Schipper et al., 2009).
AHL acylases were identified in various Gram-negative
bacteria (Ralstonia, V. paradoxus and P. aeruginosa) and in a
FEMS Microbiol Ecol 70 (2009) 1–19
high G1C Gram-positive rhizosphere isolate R. erythropolis
W2. Two enzymatic activities implied in AHL inactivation
were evidenced in this strain: an amidolytic activity, which
cleaves the amide bond of AHL, and an oxidoreductase
activity, which converts 3-oxo-AHLs to their corresponding
3-hydroxy derivatives (Uroz et al., 2005); growth on C6-HSL
as the sole carbon source is likely due to such enzymatic
activities.
Numerous bacterial species possessing the ability to
inactivate AHLs have been isolated from the rhizosphere
(d’Angelo-Picard et al., 2005; Jafra et al., 2006). AHLproducing and AHL-degrading bacteria can coexist within
the same environment, as shown within the rhizosphere of
tobacco (d’Angelo-Picard et al., 2005); thus, accumulation
of AHLs is influenced by the presence of AHL-producing
communities and AHL-degrading communities in a particular biotope.
The inactivation of AHLs can not only provide a source
of nutrients but also prevents QS signalling in neighbouring
bacteria and mitigates the bactericidal effect of 3-oxo-AHLs;
such enzymes should provide a competitive advantage to the
corresponding bacteria (Leadbetter & Greenberg, 2000;
Kaufmann et al., 2005; Yang et al., 2006). Whether AHLs
are the primary substrates for these enzymes is still unclear,
and thus their physiological function(s) remain(s) to be
elucidated. AiiA of Bacillus thuringiensis was recently shown
to be involved in rhizosphere competence, as the survival
rate of the aiiA mutant significantly decreased over time
compared with that of the wild type (Park et al., 2008b).
Cross-talk
A given AHL can be produced by several bacterial species;
for example, P. aeruginosa, Serratia liquefaciens or A. hydrophila produce C4-HSL, a molecule controlling the expression of virulence factors in these pathogens (Winson et al.,
1995; Eberl et al., 1996; Swift et al., 1997). Thus, in its
natural habitat, an AHL-producing bacterial species can
coexist with other(s) species producing identical AHLs or
structurally related AHL, and can perceive these AHLs,
leading to cross-talk (Fig. 2).
Spent culture supernatants of P. aeruginosa can activate
the production of virulence factors in Burkholderia cepacia,
an AHL-producing bacterium cohabiting with P. aeruginosa
in the lungs of cystic fibrosis patients (McKenney et al.,
1995). Moreover, P. aeruginosa-made AHLs are able to
trigger the expression of several genes of B. cepacia, including cepI, in mixed biofilms formed in vitro or in vivo on
mouse models (Riedel et al., 2001); this cross-talk seems to
be unidirectional. Long-chain AHLs made by Mesorhizobium sp. can also restore the synthesis of protease and
pyoverdin in an AHL-deficient P. aeruginosa (Krick et al.,
2007).
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
10
M. Boyer & F. Wisniewski-Dyé
Bacterial players
AHL producers
1b
AHL degrader
3a
AHL « eavesdropper »
AHL « barrier »
Root
3b
3c
1b
1a
3d
2a
2b
Soil particle
4
Fig. 2. Schematic representation of environmental factors affecting the synthesis, stability, diffusion and perception of AHL signals. An example of a
rhizosphere is depicted here, with the presence of five bacterial species: two AHL producers (ovals and rectangles), one AHL degrader (grey hexagons),
one AHL eavesdropper (circles) and one acting as an AHL barrier (grey squares). Light blue cells do not ‘quorate’ whereas green cells ‘quorate’; grey cells
do not respond to AHL. AHL and plant mimics are represented, respectively, by small dark circles and small dark triangles. The exopolysaccharides matrix is
represented by an orange area around the cells. (1) Action of biotic factors, such as diffusion (1a) and advection (1b). (2) Influence of spatial distribution of
the cells, with cells in biofilm (2a) and free-living cells in a limited volume (2b). (3) Influence of the bacterial community with AHL degradation (3a), crosstalk (3b), AHL interception (3c), biological barrier to AHL diffusion (3d). (4) Influence of eukaryotes (such as plant-producing AHL mimics).
Interpopulation signalling was also evidenced in the
rhizosphere of wheat and tomato (Pierson et al., 1998;
Steidle et al., 2001).
Bacterial AHL mimics
Phenethylamide metabolites produced by the marine Grampositive bacterium Halobacillus salinus inhibit QS-regulated
phenotypes, such as bioluminescence in Vibrio harveyi and
violacein production in Chromobacterium violaceum; these
nontoxic secondary metabolites may act as QS antagonists
by competing with AHL for receptor binding (Teasdale
et al., 2009). Diketopiperazines have also been isolated
from supernatants of Proteus mirabilis, Citrobacter freundii,
Enterobacter agglomerans and P. putida (Holden et al., 1999;
Degrassi et al., 2002). Some diketopiperazines are capable of
activating or antagonizing some LuxR-based QS systems,
such as the C4-HSL-dependent swarming of S. liquefaciens
(Holden et al., 1999; Degrassi et al., 2002). Although the
physiological role of these diketopiperazines is yet to be
established, their activity suggests the existence of cross-talk
among bacterial signalling systems.
Signal interception
Some bacteria, although they do not produce any AHL, can
detect these signals and induce specific genes accordingly,
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
and so act as eavesdroppers. For example, Escherichia coli
does not make AHL, but possesses a LuxR homologue, SdiA,
able to interact with exogenous AHLs (Yao et al., 2006).
SdiA is an orphan LuxR, a term used to specify that the
bacterium has no AHL synthase or that the LuxR regulator
has no cognate AHL synthase. The SdiA/AHL complex
regulates specific target genes, notably genes involved in
acid tolerance (Van Houdt et al., 2006). This strategy allows
E. coli to save the energetic cost linked to AHL synthesis, but
the SdiA/AHL regulation only occurs in the presence of AHL
producers. Thus, E. coli is able to intercept the signals and
could consequently interfere with the accumulation of AHLs
produced by other bacterial populations.
Barrier to AHL diffusion
Whether the presence of non-AHL-producing and non-AHLdegrading bacteria affects the induction of AHL-mediated
gene expression was investigated. Using artificial microcolonies of mixed species, containing an AHL producer and an
AHL biosensor, covered with layers of non-AHL-producing
cells, it was shown that the presence of the non-AHL-producing cells enhanced green fluorescence, the biosensor response
(Mason et al., 2005). Thus, it is likely that non-AHL-producing cells can act as a barrier to AHL movement, allowing
AHL to accumulate within the microcolony, and can thus
affect AHL-mediated responses.
FEMS Microbiol Ecol 70 (2009) 1–19
11
Cell–cell signalling in bacteria
Influence of eukaryotes on bacterial
communication
AHL inactivation
Hydrolysis of the lactone ring of AHLs occurs in serum
samples of mammals and in animal cell lines expressing
paraoxonases, enzymes that have no homologues in the
prokaryotic kingdom (Ozer et al., 2005; Yang et al., 2005).
AHL inactivation could be a defence mechanism impeding
the QS-regulated expression of bacterial virulence factors
(Stoltz et al., 2007; Teiber et al., 2008). Some plants also
display the ability to inactivate AHLs, but the mechanisms
underlying this ability remain to be described (Delalande
et al., 2005; Götz et al., 2007).
Microorganisms residing within biofilms are more resistant to antibacterial agents; the finding that AHLs are
involved in biofilm development has thus provided a novel
mechanism of biofilm control. 3oxo,AHLs were found to
rapidly react with halogenated compounds, such as HOCl
and HOBr, extensively used for microbial control in industrial systems (Michels et al., 2000; Borchardt et al., 2001).
These compounds can also be generated by a variety of
organisms; the natural haloperoxidase systems of the marine
alga Laminaria digitata are capable of mediating the inactivation of 3oxo,AHLs, and may prevent biofouling on the
algal surface (Borchardt et al., 2001).
Algal compounds
Halogenated furanones, compounds naturally produced by
the red macroalga Delisea pulchra, were the first molecules
found to interfere with QS-regulated phenotypes; these
compounds, which display structural homologies with
AHLs, can inhibit swarming motility in S. liquefaciens,
reduce virulence and bioluminescence in V. harveyi and
alter the architecture of P. aeruginosa biofilms (Givskov
et al., 1996; Manefield et al., 2000; Hentzer et al., 2002).
Halogenated furanones inhibit QS by directly interacting
with LuxR homologues, triggering LuxR turnover (Manefield et al., 2002). This type of secondary metabolite is
thought to protect D. pulchra from bacterial colonization
(Kjelleberg et al., 1997). This initial finding that natural
compounds could interfere with AHL signalling accelerated
the screening for QS inhibitors with the aim of blocking QS
in bacterial pathogens, without the risk of emergence of
resistance, in contrast to antibiotics.
The unicellular soil-freshwater alga Chlamydomonas
reinhardtii also secretes substances that mimic bacterial
AHLs (Teplitski et al., 2004). More than a dozen unidentified substances are capable of specifically stimulating the
LasR or CepR AHL-biosensor strains, but not the LuxR,
AhyR or CviR biosensors, suggesting that these compounds
FEMS Microbiol Ecol 70 (2009) 1–19
will affect QS signalling differently. Moreover, treatment of
Sinorhizobium meliloti, a soil bacterium establishing a symbiosis with some leguminous plants, with a C. reinhardtii
partially purified AHL mimic affects the accumulation of
some proteins that are altered in response to the bacterium’s
own AHL signals (Teplitski et al., 2004). As there is no
obvious purpose for C. reinhardtii to interfere with bacterial
signalling, the effect of these compounds on signalling might
be coincidental.
Plant-made compounds
Plants such as pea, vetch, soybean, rice and Medicago
truncatula can produce compounds acting as AHL mimics
as they can interfere with some AHL biosensors (Teplitski
et al., 2000). A large screening aimed at identifying QS
inhibitors revealed that garlic extracts contain such compounds (Rasmussen et al., 2005a). The QS-regulated
production of exopolysaccharides of S. meliloti is inhibited
by L-canavanine, an arginine analogue that is exclusively
produced by leguminous seeds, such as those of Medicago
sativa (Keshavan et al., 2005). Although the structure of the
active compounds has not been elucidated in most studies,
the existence of such compounds suggests that plant–bacteria interactions can be manipulated by plants.
Another level of QS-interference by plant metabolites is
exemplified by the plant–A. tumefaciens interaction. This
crown-gall-causing agent transfers a part of its pTi, the
T-DNA, into the genome of plant cells, leading to anarchic
growth of plant cells; T-DNA also codes for proteins
involved in the biosynthesis of opines, compounds that are
specifically catabolized by A. tumefaciens due to genetic
determinants localized on the pTi. The conjugative transfer
of pTi, which is QS regulated via the traI/traR system, is also
influenced by opines. Thus, the expression of the tra operon
requires the presence of two signals: a plant signal, an opine,
indicates that the nutrient-rich place is favourable to
conjugation, and a signal produced by the recipient
bacterial cells, an AHL, triggers conjugation at a high cell
density (Zhang et al., 1993; Fuqua & Winans, 1994; Piper &
Farrand, 2000). Plant-made GABA and salicylic acid
also act on the pTi transfer by inducing the expression of
the AttM endogenous lactonase (see AHL diffusion and
transport through membrane) (Chevrot et al., 2006; Yuan
et al., 2008).
Fungal compounds
Extracts of 50 members of the genus Penicillium were
screened for QS-inhibitory compounds; several fungi were
found to produce such inhibitory activities and two of the
compounds were identified: penicillic acid and patulin
(Rasmussen et al., 2005b). These two compounds can
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
12
inhibit expression of QS-controlled genes in P. aeruginosa, as
revealed by DNA microarray transcriptomics; patulin can
enhance biofilm susceptibility to tobramycin treatment.
Patulin is thought to accelerate LuxR turnover, as observed
previously with halogenated furanones (Rasmussen et al.,
2005b).
Animal compounds
Pseudomonas aeruginosa seems to be able to perceive its host
immune activation. Interferon-g (IFN-g), signalling proteins synthesized during the host immune response, can
activate the production of virulence factors via the rhlI/rhlR
system (Wu et al., 2005; Wagner et al., 2006). IFN-g are
recognized by a major outer membrane protein, OprF,
which, by an unknown mechanism, drives rhlR overexpression. rhlI expression triggers the expression of QS-dependent virulence factors, notably PA-I lectin and pyocyanin. In
contrast, 3oxo,C12-HSL stimulate the production of IFN-g
by T lymphocytes (Smith et al., 2002). This molecular
dialogue illustrates the pivotal role of QS in the establishment of the interaction between a bacterium and its
eukaryotic host.
Cyclic dipeptides (diketopiperazines), like the ones produced by some bacterial species (see Regulation of AHL
production by other endogenous signals and Biotic factors
within the bacterial community), have also been evidenced
in yeasts, lichens, fungi and in some mammalian tissues,
suggesting that these eukaryotic diketopiperazines could
also interfere with bacterial communication (Prasad, 1995).
Recently, the alkaloid solenopsin A, produced by the fire
ant Solenopsis invicta, was shown to efficiently disrupt QS in
P. aeruginosa, by targeting the rhl QS system (Park et al.,
2008a).
Exploitation of AHLs by eukaryotes?
Whether AHL are dedicated only to bacterial signalling is
certainly questioned, with several studies reporting that
some eukaryotes are able to perceive and to respond to
AHLs. Indeed, 3oxo,C12-HSL produced by P. aeruginosa has
an immunomodulatory activity and might contribute to
bacterial pathogenesis as a virulence determinant per se
(Telford et al., 1998; Smith et al., 2002). In the marine
environment, the zoospores of the green seaweed Ulva are
attracted by synthetic AHLs, and by AHLs released by
bacterial biofilms; when zoospores detect AHLs, their swimming rate is reduced and this results in accumulation of cells
at the source of the AHL. It is probable that AHLs act as cues
for the settlement of zoospores influencing their biogeography, rather than being directly involved as a signalling
mechanism (for a review, see Joint et al., 2007).
c 2009 Federation of European Microbiological Societies
Journal compilation Published by Blackwell Publishing Ltd. No claim to original French government works
M. Boyer & F. Wisniewski-Dyé
In the rhizosphere, several AHLs were shown to trigger
significant changes in the accumulation of 4 150 proteins
of the model leguminous plant M. truncatula (Mathesius
et al., 2003); some of these proteins are involved in defence,
stress response, transcriptional regulation and hormonal
response. In addition, exposure to AHLs was found to
induce changes in the secretion of compounds by the plants
that mimic QS signals and thus have the potential to disrupt
QS in associated bacteria (Mathesius et al., 2003).
Inoculation of AHL-producing S. liquefaciens on tomato
plants increases their systemic resistance against the fungal
leaf pathogen, Alternaria alternata, whereas the AHL-negative mutant S. liquefaciens is less effective in reducing
symptoms. Moreover, AHL molecules systemically induce
salicylic acid and ethylene-dependent defence genes (Schuhegger et al., 2006). Thus, AHL molecules play a role in the
biocontrol activity of rhizobacteria through the induction of
systemic resistance to pathogens. The contact of Arabidopsis
thaliana roots with C6-HSL results in distinct transcriptional changes in roots and shoots, alterations of the auxin
to cytokinin ratio and increase of root elongation (von Rad
et al., 2008). C6-HSL may contribute to tuning plant growth
to the microbial composition of the rhizosphere.
Thus, eukaryotes have an extensive range of functional
responses to AHLs that may play important roles in the
beneficial or the pathogenic outcomes of eukaryote–prokaryote interactions.
Conclusion
Initially, regulation through QS had been perceived as a
relatively simple model involving an AHL synthase, an AHL
signal and a LuxR-type regulator activating specific genes at
a high cell density. The overall picture is far more complex:
QS genes are embedded in a network of global regulation,
where the synthesis of the AHL signal is highly responsive to
the growth phase and to environmental factors; intertwined
QS systems can coexist within a single bacterium allowing
the fine tuning of AHL synthesis and consequently the
expression of QS-regulated phenotypes. QS regulation networks seem to be all the more complex as they appear to be
strain specific with various AHL patterns and distinct QS
regulons displayed by strains of the same species (Boyer
et al., 2008; Steindler et al., 2008).
In natural biotopes, bacterial signalling can be compromised by many factors, whether abiotic or biotic; indeed,
AHL accumulation relies on the stability, diffusion, sequestration, inactivation of AHL and the spatial distribution of
cells. Moreover, the signalling process can undergo interferences such as cross-talk events and various molecules mainly
produced by eukaryotes, suggesting that eukaryotes have
evolved strategies to interfere with bacterial signalling in
order to protect themselves from pathogenic bacteria.
FEMS Microbiol Ecol 70 (2009) 1–19
Cell–cell signalling in bacteria
Hence, it is clear that AHL signalling is far more than a
matter of quorum.
Given the complexity of regulatory networks and the
number of factors affecting QS signalling, modelling approaches are undertaken to study the transition to QS
(Goryachev et al., 2005) or to follow the evolution of AHL
signals in conjunction with the spatial distribution of cells
and environmental factors (Hense et al., 2007). In this
context, the concept of efficiency sensing, a concept that
unifies both QS and diffusion sensing, was proposed;
whereas QS postulates that bacteria sense their density to
coordinate a concerted behaviour, diffusion sensing proposes that sensing is an autonomous activity used to detect
mass-transfer limitation. Efficiency sensing would enable
cells to sense cell density, diffusion limitation and cell
distribution (clustering), and includes the potential for cooperation as clusters may help protect against interference
by other species and cheaters (Hense et al., 2007).
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