MINIREVIEW

Quorum sensing: the many languages of bacteria

Nicola C. Reading & Vanessa Sperandio
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence: Vanessa Sperandio,

Department of Microbiology, University of
Texas Southwestern Medical Center, 5325
Harry Hines Blvd, Dallas, TX 75390-9048,
USA. Tel.: 1214 648 1603; fax: 1214 648
5905; e-mail: Vanessa.Sperandio@
UTSouthwestern.edu
Received 6 September 2005; revised 29
September 2005; accepted 1 October 2005.
First published online 9 November 2005.
doi:10.1111/j.1574-6968.2005.00001.x
Editor: Ian Henderson

Abstract
In the conventional view of prokaryotic existence, bacteria live unicellularly, with
responses to external stimuli limited to the detection of chemical and physical
signals of environmental origin. This view of bacteriology is now recognized to be
overly simplistic, because bacteria communicate with each other through small
hormone-like organic compounds referred to as autoinducers. These bacterial
cell-to-cell signaling systems were initially described as mechanisms through which
bacteria regulate gene expression via cell density and, therefore, they have been
collectively termed quorum sensing. The functions controlled by quorum sensing
are varied and reflect the needs of a particular species of bacteria to inhabit a given
niche. Three major quorum-sensing circuits have been described: one used
primarily by Gram-negative bacteria, one used primarily by Gram-positive
bacteria, and one that has been proposed to be universal.

Keywords
quorum sensing; autoinducer; hormone; cellto-cell signaling.

Introduction
Quorum sensing (QS) is a cell-to-cell signaling mechanism
that refers to the ability of bacteria to respond to chemical
hormone-like molecules called autoinducers. When an autoinducer reaches a critical threshold, the bacteria detect and
respond to this signal by altering their gene expression. QS
was first described in the regulation of bioluminescence in
Vibrio fischeri and Vibrio harveyi (Nealson et al., 1970;
Nealson & Hastings, 1979), and since then shown to be a
widespread mechanism of gene regulation in bacteria. In this
review, we will explore several QS systems used by bacteria;
the LuxR/I-type systems, primarily used by Gram-negative
bacteria, in which the signaling molecule is an acyl-homoserine lactone (AHL), the peptide signaling systems used
primarily by Gram-positive bacteria, the luxS/AI-2 signaling
used for interspecies communication, and the AI-3/epinephrine/norepinephrine interkingdom signaling system.

The LuxR/I signaling system

The LuxR/I system was the first one to be described in V.
fischeri (Nealson et al., 1970). The luciferase operon in V.
fischeri is regulated by two proteins, LuxI, which is responsible for the production of the AHL autoinducer, and LuxR,
FEMS Microbiol Lett 254 (2006) 111

which is activated by this autoinducer to increase transcription of the luciferase operon (Engebrecht et al., 1983;
Engebrecht & Silverman, 1984). Since this initial description, homologs of LuxRLuxI have been identified in other
bacteria, and in all of these LuxRLuxI systems, the bacteria
produce an AHL autoinducer, which binds to the LuxR
protein and regulates the transcription of several genes
involved in a variety of phenotypes. These include the
production of antibiotics in Erwinia, motility in Yersinia
pseudotuberculosis, and pathogenesis and biofilm formation
in Pseudomonas aeruginosa, among others (Davies et al.,
1998; de Kievit & Iglewski, 2000; Parsek & Greenberg, 2000)
(Fig. 1).
The LuxI-type proteins are the AHL synthases. AHLs have
a conserved homoserine lactone ring connected through an
amide bond to a variable acyl chain. Acyl chains vary in
number of carbons from four to 18 and the third position
may or may not be modified (carbonyl group, hydroxyl or
fully reduced). Different acyl chains ensure that different
AHLs will be recognized by different LuxR-type proteins.
The substrate used by LuxI-type proteins for AHL synthesis
is S-adenosyl-methionine (SAM) to synthesize the homoserine lactone ring, and the acyl chains come from lipid
metabolism, carried by various acyl-carrier proteins
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N.C. Reading & V. Sperandio

Luminescence structural genes

R

lux
High cell density
(lots of AHL)
LuxR binds to AHL

lux

LIGHT

Fig. 1. Model of bioluminescence activation in Vibrio fischeri by the

LuxR/I quorum-sensing system. In high cell density, the acyl-homoserine
lactone (AHL) autoinducer binds to LuxR. LuxR complexed with AHL then
activates transcription of itself and the luciferase operon.

(Kalogeraki & Winans, 1995; More et al., 1996; Parsek et al.,

1999).
The LuxR-type proteins are transcription factors, which,
upon binding to the AHL signal, regulate transcription of
their target genes. It has been shown that AHL binding to
these proteins stabilizes them; otherwise, in the absence of
signal, they are targeted to degradation (Zhu & Winans,
1999, 2001; Zhang, 2002). The LuxR-type proteins usually
recognize a specific AHL. Because of this feature, this
signaling system has been primarily associated with intraspecies signaling. However, there are examples of LuxR-type
proteins (such as SdiA described below) that recognize more
than one AHL and are primarily involved in interspecies
signaling.
Escherichia coli and Salmonella have a LuxR homolog,
SdiA (Wang et al., 1991), but do not have a luxI gene, and do
not produce AHLs (Swift et al., 1999; Michael et al., 2001).
The E. coli sdiA gene initially was isolated as a regulator of
the cell division genes ftsQAZ (Wang et al., 1991). Although
a cloned sdiA gene on a multicopy plasmid can upregulate
expression of ftsQAZ genes, an sdiA mutant has no apparent
cell division defects (Wang et al., 1991). Kanamaru et al.
(2000) found that expression of SdiA from a high copy
number plasmid in enterohemorrhagic E. coli (EHEC)
caused abnormal cell division, reduced adherence to cul2005 Federation of European Microbiological Societies
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tured epithelial cells, and reduced expression of the intimin

adhesin protein and the EspD protein, both of which are
encoded on the locus of enterocyte effacement (LEE)
pathogenicity island. However, no sdiA EHEC mutant was
constructed and tested, and, consequently, the effects seen
could be artifacts because of the abnormally high expression
of SdiA. Because no E. coli genes from either EHEC or K-12
have yet been demonstrated to be regulated by the single
chromosomal copy of sdiA, Ahmer (2004) recently concluded that there are no confirmed members of a SdiA
regulon in this species. The precise role of SdiA in QS was
elusive for several years until Michael et al. (2001) reported
that SdiA is not sensing an autoinducer produced by
Salmonella itself, but rather AHLs produced by other
bacterial species. SdiA regulates a few genes in Salmonella
including one gene potentially involved in resistance to
human complement, rck (Ahmer et al., 1998). However,
mutation of the sdiA gene had no effect on virulence of
Salmonella in mouse, chicken or bovine models of disease
(Ahmer, 2004).
One of the best characterized LuxR/I-type QS systems is
in P. aeruginosa. Pseudomonas aeruginosa uses QS to activate
several genes involved in colonization and persistence within
the host (Parsek & Greenberg, 2000). Pseudomonas aeruginosa is an opportunistic pathogen of immunocompromised
individuals, including those with burns, human immunodeficiency virus, or cystic fibrosis (Parsek & Greenberg,
2000). The morbidity and mortality associated with cystic
fibrosis, in particular, are because of the chronic colonization of the pulmonary airways by P. aeruginosa. QS controls
production of an array of virulence factors (elastase, exotoxin A, piocianin, etc.) and biofilm development in this
organism. Disruption of the QS system diminishes P.
aeruginosa virulence in plants and animals and inhibits
biofilm formation (Rahme et al., 1995; Costerton et al.,
1999; Tan et al., 1999). The QS system of P. aeruginosa is very
complex and hierarchical. Pseudomonas aeruginosa produces
two AHLs, N-(3-oxododecanoyl)-L-homoserine lactone
(3OC12-HSL) and N-butanoyl-L-homoserine lactone (C4HSL) (Pearson et al., 1994, 1995). These AHLs bind to and
activate LasR and RlhR transcription factors, respectively
(Parsek & Greenberg, 2000). LasR complexed with 3OC12HSL activates the transcription of rhlR and rlhI (RhlI is the
synthase for C4-HSL). Therefore, LasR is at the very top of
the P. aeruginosa QS signaling cascade (Parsek & Greenberg,
2000).
Some bacteria have the ability to disrupt QS signaling by
degrading AHL autoinducers. The soil bacterium Bacillus
produces a lactonase enzyme that hydrolyzes the lactone
ring of AHLs. This lactonase enzyme probably interferes
with AHL signaling by other bacterial species with which
Bacillus competes in nature (Dong et al., 2001). In addition,
transgenic plants expressing the Bacillus lactonase show
FEMS Microbiol Lett 254 (2006) 111

Quorum sensing: the many languages of bacteria

resistance to QS-dependent bacterial infection (Dong et al.,

2001).
The LuxR/I-type QS systems have been linked to interkingdom signaling. The marine macroalga Delisea pulchra
blocks interaction of the plant pathogen Serratia liquifaciens
by producing a halogenated furanone that acts as a competitive inhibitor of the bacteriums AHL-based QS system
(Rasmussen, 2000). Another example of crosskingdom
signaling and QS interference has been documented by the
administration of AHLs to the model legume Medicago
truncatula (Mathesius et al., 2003). These plants respond to
AHL administration in a global manner by changing their
accumulation of 150 proteins, including auxin-responsive
and flavonoid synthesis proteins. In addition, exposure of
plants to AHLs induced the secretion of compounds that
mimic QS signals and thus have the potential to disrupt QS
in associated bacteria.
There are also a growing number of reports indicating that
bacterial AHLs modulate gene expression of mammalian
organisms. Most of these studies implicate the 3OC12-HSL
of P. aeruginosa as influencing the production of several
cytokines by immune cells in vitro and in vivo (Telford,
1998; Smith et al., 2001, 2002a, b; Ritchie et al., 2003; Tateda,
2003). However, some of these reports appear to be contradictory with respect to whether this crosskingdom signaling is
beneficial or detrimental to the host. Telford (1998) reported
that 3OC12-HSL inhibited the production of interleukin-12
(IL-12) and tumor necrosis factor a by lipopolysaccharidestimulated macrophages. Using an in vitro model of B-cell
activation, these authors also reported that production of
immunoglobulin G1 antibodies and IgE was elevated by
administration of 3OC12-HSL, leading this group to propose
that this AHL acts to modulate a T-cell-mediated immune
response from a type 1 (Th1, proinflammatory) response to a
type 2 (Th2, anti-inflammatory) response. In contrast, this
autoinducer has also been shown to increase the production
of cyclo-oxygenase-2 and prostaglandin E2 in human lung
fibroblasts (Smith et al., 2002a, b) and several proinflammatory chemokines, including IL-8, in human bronchiolar
epithelial cells and lung fibroblasts (Smith et al., 2001). These
results led Smith et al. (2001) to propose that the severe lung
damage that accompanies P. aeruginosa infections is caused
by an exuberant neutrophil response stimulated by AHLinduced IL-8. These conflicting data may be the result of
different host cell types or concentrations of AHLs used.
Mammalian cell interference could also offer an explanation
to the contradictory results reported concerning 3OC12-HSL
modulation of immune responses. Chun et al. (2004)
reported that human airway epithelia inactivated 3OC12HSL. They also reported that the AHL inactivation capability
varied widely in different cell types. Interestingly, cells derived
from human epithelia exposed to environmental pathogens,
such as A549 human lung cells and CaCo-2 human colonic
FEMS Microbiol Lett 254 (2006) 111

epithelial cells, showed the greatest levels of 3OC12-HSL

inactivation. One can speculate that AHL inactivation occurs
primarily in cells likely to come in contact with bacteria, and
that this activity might play a role in the host innate defenses
against pathogens.
The combined studies make a compelling case that
bacterial autoinducers can modulate gene expression in host
cells. However, it remains unclear as to whether these AHLs
actually enter mammalian cells or exert their effects by
binding to host cell surface receptors. This question was
recently addressed in a report by Williams et al. (2004), who
demonstrated that P. aeruginosa 3OC12-HSL can both enter
mammalian cells and activate chimeric transcriptional factors based on its cognate LasR transcriptional activator. The
autoinducer promoted nuclear localization of the chimeric
LasR, and these LasR-based proteins activated the transcription of reporter fusions containing LasR-DNA target sequences. Although specific mammalian receptor proteins
for bacterial autoinducers remain to be identified, the
observation that the TraR autoinducer-binding domain
resembles a GAF or PAS domain (involved in small molecule
sensing in mammalian signaling proteins) might offer clues
for possible autoinducer targets within mammalian cells
(Vannini et al., 2002). In summary, eukaryotes seem to have
a range of functional responses to AHLs that may play
important roles in the beneficial or pathogenic outcomes of
eukaryoteprokaryote interactions.

Quorum sensing in Gram-positive

organisms
Quorum sensing in Gram-positive organisms relies on
autoinduction by small peptides, which interact with twocomponent systems ultimately regulating gene transcription. These small peptides are usually products of oligopeptides that are cleaved and/or further modified before being
exported from the bacterium by transporters. At threshold
concentrations, the peptides are recognized by sensor kinases that initiate phospho-transfer to a response regulator.
The peptides involved in Gram-positive QS are often
specific for their cognate receptors. The following are several
important examples of Gram-positive systems.
Staphylococcus aureus is one of the most common commensal Gram-positive organism in humans; however, it can
lead to pneumonia, endocarditis, osteomyelitis, wound
infections, and other complications. The QS system that
this bacterium utilizes is one of the most studied systems in
Gram-positive organisms. The accessory gene regulator
(Agr) system regulates toxin and protease secretion in
staphylococci. At low cell density, the bacteria express
proteins required for attachment and colonization, and as
the cell density becomes higher, this expression profile
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switches to express proteins involved in toxin and protease

secretion (Novick, 2003).
The S. aureus autoinducing peptide (AIP) is encoded by
the agrD gene. AgrB then adds a thiolactone ring to this
peptide and transports the AIP out of the cell. The AIP
works with its receptor, sensor kinase ArgC and ArgCs
cognate response regulator, ArgA. Upon AIP binding to
ArgC, ArgC transfers a phosphate to ArgA, which activates
transcription of the arg operon for autoregulation and in
addition activates transcription of the RNAIII, regulatory
RNA, which in turn leads to the repressed expression of cell
adhesion factors and induced expression of secreted factors
(Novick, 2003).
The specificity of the Arg system is such that, not only will
noncognate AIP and receptors not specifically recognize
each other, but each AIP will also repress the other AIPs by
competitive binding to noncognate receptors. Thus far,
there are four known specificity groups that have been
characterized by sequence variation, and each group seems
to result in a different disease. For example, S. aureus group
III seems to correlate with menstrual toxic shock syndrome,
type III with necrotizing pneumonia, and type Is and type
IIs have been associated with vancomycin resistance. Thus,
in coinfection models, one group will out-compete the other
leading to only one disease progression. This might have
allowed evolution of S. aureus into suited environments
(Novick, 2003).
Enterococcus faecalis are commensal organisms of the
gastrointestinal tract that are often seen in nosocomial
infections like surgical infections and urinary tract infections. Cytolysin, the major virulence factor in E. faecalis,
possesses both bacteriocin and hemolytic activity, making it
lethal to many eukaryotic cells as well as toxic to many
Gram-positive bacteria. The cytolysin also serves as an
autoinducer for QS induction of the cytolysin operon.
Composed of two subunits, CylLL and CylLS, which are
posttranslationally modified in order to form their mature
extracellular form, control of the cytolysin is regulated by a
threshold concentration of the mature form of CylLS (Haas
et al., 2002). CylLL has been shown to bind strongly to target
cell membranes, allowing free CylLS to accumulate above a
critical induction threshold (Coburn et al., 2004). This
subunit acts as an autoinducer that activates transcription
from the cyl promoter creating high levels of cytolysin when
conditions are appropriate. CylR1 and CylR2 are genes
transcribed from the cylL genes, and mutation in either one
leads to derepression of the cyl operon. They comprise a
two-component system, although lacking similarity to twocomponent regulators (Haas et al., 2002).
Streptococcus pneumoniae was one of the original Grampositive systems characterized. Only under certain conditions, i.e. high cell density, was S. pneumoniae capable of
competence (Tomasz & Hotchkiss, 1964; Tomasz, 1965;
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N.C. Reading & V. Sperandio

Tomasz & Mosser, 1966). Subsequently, an activator was

discovered that was capable of inducing competence in S.
pneumoniae as a substitute for actual cells. While original
characterization of the activator proved difficult, the discovery of an ABC transporter that secreted the activator,
comA, revealed a class of ABC transporters that contained
N-terminal proteolytic domains (Hui & Morrison, 1991;
Havarstein et al., 1995; Zhou et al., 1995). This led to the
characterization of the activator as competence inducing
factor (CSP), a cationic, and 17 amino acid peptide that
contains a glygly leader sequence, which is cleaved from the
original precursor (Havarstein et al., 1995).
The structural gene of CSP, comC, lies in an operon with
comD, which encodes a histidine kinase, and comE, encoding
a response regulator (Pestova et al., 1996). ComD serves as
the receptor for CSP (Havarstein et al., 1996). Currently, 10
different comD alleles that encode different ComD specificities, primarily in the N-terminal regions, have been
identified. When phosphorylated, ComE activates the
comCDE operon in autoregulatory fashion in addition to
comAB and the comX, a regulator that induces genes
involved in competence. In addition, ComE induces genes
involved in stress responses and protein synthesis (Lee &
Morrison, 1999; Peterson, 2004).
Competence inducing factors have been shown to be
highly specific, so that a CSP from one species will only
specifically recognize its own cognate histidine kinase receptor. This specificity means that often even different
isolates of the same species have distinctions (Havarstein
et al., 1997).
Although the CSPQS system in streptococci is a classic
example of competence regulation, in a recent transcriptome analysis, a small fraction of the 124 genes induced by
the CSP system are actually required for transformation.
This indicates that the CSP system might be involved in
other types of regulation. Indeed, initial studies have already
implicated the importance of the CSPQS system in adaptive environments and for functions such as virulence and
biofilm formation (Cvitkovitch et al., 2003; Peterson, 2004).

The LuxS/AI-2 signaling system

Vibrio harveyi is a marine bacterium that controls bioluminescence through QS. Vibrio harveyi QS system constitutes a
mix between components of Gram-positive and Gramnegative systems. It has two QS systems: system 1 in which
the autoinducer (AI-1) is an AHL, and is primarily involved
in intraspecies signaling (Bassler et al., 1994); system 2, in
which the autoinducer is a furanosyl borate diester (Chen
et al., 2002) involved in interspecies signaling (Surette &
Bassler, 1998). Vibrio harveyi has two hybrid sensor kinases,
LuxN and LuxQ, which sense AI-1 and AI-2, respectively. In
the absence of signal, these proteins are intrinsic kinases and
FEMS Microbiol Lett 254 (2006) 111

Quorum sensing: the many languages of bacteria

(a)

(b)

LsrB +

LuxP

Lsr C

LsRA
ATP

Lsr C

AI-2

LuxQ
AI-2

LsrB

LsrK

ADP

ATP
ADP

Sensor
kinase
H
LuxU

AI-1

LuxN
H
Sensor
kinase

LsrR

HTH
LuxO

lsrK

lsrRl

srA

lsrC

lsrD

lsrB

lsrF

lsrGl srE

ncRNAs

LuxR
luxCDABEGH
Fig. 2. The LuxS/AI-2 quorum-sensing system. (a) Vibrio harveyi uses two sensor kinases, LuxN and LuxQ, to recognize AI-1 and AI-2, respectively. LuxQ
recognizes AI-2 complexed with its periplamic receptor LuxP. Upon sensing these signals, these kinases become phosphatases and this complex
phosphorelay system (through LuxU and LuxO) is dephosphorylated. Dephosphorylated LuxO no longer activates transcription of ncRNAs.
Consequently, LuxR mRNA is no longer degraded, and LuxR activates transcription of the luciferase operon. (b) In Salmonella and Escherichia coli the
AI-2 receptor is the LsrB periplasmic protein. Upon binding LsrB, AI-2 is transported inside the cell via the Lsr ABC transport system. AI-2 is then
phosphorylated by LsrK, and presumed to interact with LsrR. LsrR is a transcriptional repressor of the lsr operon. Upon complexing of Lsr to AI-2, LsrR no
longer represses lsr transcription.

phosphorylate a complex phosphorelay system, with LuxU

and LuxO (an enhancer-binding protein) as intermediaries
(Bassler et al., 1993, 1994; Freeman & Bassler, 1999; Freeman
et al., 2000). Phospho-LuxO in conjunction with s54 then
activates transcription of small regulatory RNAs, which
destabilize the message of the LuxR protein, which in turn
no longer can activate transcription of the luciferase operon
(Lenz et al., 2004). Upon interaction with their cognate
autoinducers, these sensors behave as phosphatases and the
system is dephosphorylated, allowing LuxR to activate
bioluminescence (Fig. 2).
Whether AI-1 directly interacts with LuxN remains to be
demonstrated. The AI-2 receptor is the periplasmic protein
LuxP, which resembles the ribose-binding protein RbsB
(Chen et al., 2002). LuxP complexes with LuxQ controlling
whether LuxQ behaves as a kinase or phosphatase according
to the concentration of AI-2 present (Neiditch et al., 2005).
The AI-1 synthase is the LuxM gene, which does not belong
to the same family of the LuxI-type proteins (Bassler et al.,
1993). AI-2 is synthesized by the LuxS enzyme (Surette &
Bassler, 1998; Surette et al., 1999). LuxS is an enzyme
involved in the metabolism of SAM; it converts S-ribosylFEMS Microbiol Lett 254 (2006) 111

homocysteine into homocysteine and 4,5-dihydroxy-2,3pentanedione (DPD). DPD is a very unstable compound
that reacts with water and cyclizes to form several furanones
(Schauder et al., 2001; Winzer, 2002; Sperandio et al., 2003),
one of which is thought to be the precursor of AI-2
(Schauder et al., 2001). The AI-2 structure has been solved
by cocrystallizing this ligand with its receptor LuxP in V.
harveyi and reported to be a furanosyl borate diester (Chen
et al., 2002). However, LuxP homologs, as well as homologs
from this signaling cascade, have only been found in Vibrio
sp. Several bacterial species harbor the luxS gene, and have
AI-2 activity as measured using a V. harveyi bioluminescence assay (Schauder & Bassler, 2001; Xavier & Bassler,
2003). However, the only genes shown to be regulated by AI2 in other species encode for an ABC transporter in
Salmonella typhimurium named Lsr (LuxS-regulated), responsible for the AI-2 uptake (Taga et al., 2001). This ABC
transporter is also present in E. coli and shares homology
with sugar transporters. Once inside the cell, AI-2 is
modified by phosphorylation and proposed to interact with
LsrR, which is a SorC-like transcription factor involved in
repressing expression of the lsr operon (Taga et al., 2001,
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2003) (Fig. 1). Several groups have been unable to detect the
furanosyl borate diester, proposed to be AI-2, in purified
fractions containing AI-2 activity from Salmonella and E.
coli sp. (as measured using the V. harveyi bioluminescence
assay) (Schauder et al., 2001; Winzer, 2002; Sperandio et al.,
2003). These fractions only yielded several furanones that
did not contain boron. These results can be explained now
that AI-2 has been cocrystallized with its receptor (the
periplasmic protein LsrB) in Salmonella. In these studies
the LsrB ligand was not the furanosyl borate diester, but 2R,
4S-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran (Miller
et al., 2004), consistent with what has been observed in AI2 fractions of Salmonella and E. coli (Schauder et al., 2001;
Winzer, 2002; Sperandio et al., 2003). This scenario is
fundamentally different from AI-2 detection in V. harveyi,
and raises the question whether all bacteria may actually use
AI-2 as a signaling compound, or whether it is released as a
waste product or used as a metabolite by some bacteria,
rather than a signal (Winzer, 2002; Winzer et al., 2002).
Diverse roles in signaling have been attributed to AI-2 in
other organisms by comparing luxS mutants with wild-type
strains and complementing these mutants either genetically
or with spent supernatants (Xavier & Bassler, 2003). Several
of these studies comprised transcriptome analysis measuring genes differentially expressed between wild-type strains
and the luxS mutants. Given that LuxS is not devoted to AI2 production, it is in fact an enzyme involved in the
biochemical pathway for detoxification of SAM. Consequently, altered gene expression because of a luxS mutation
will comprise both genes affected by QS per se and genes
differentially expressed because of the interruption of this
metabolic pathway. To address which genes are in fact
regulated through AI-2 signaling, one has to use pure AI-2
signal. Hence, the only two phenotypes shown to be AI-2
dependent, using either purified or in vitro synthesized AI-2,
are bioluminescence in V. harveyi (Schauder et al., 2001) and
expression of the lsr operon in S. typhimurium (Taga et al.,
2001).

The AI-3/epinephrine/norepinephrine
signaling system
This QS system was first discovered by serendipity as being
associated with the LuxS system. LuxS is not devoted solely
to AI-2 production; it is in fact an enzyme involved in the
activated methyl pathway which is involved in the synthesis
of methionine and SAM. Consequently, altered gene expression because of a luxS mutation will involve genes affected
by QS per se and genes differentially expressed because of the
interruption of this metabolic pathway. A luxS mutant will
accumulate S-ribosyl-homocysteine within the cell because
it is unable to catalyze its conversion to homocysteine. This
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N.C. Reading & V. Sperandio

would cause the levels of homocysteine to diminish within

the cell. Inasmuch as homocysteine is used for the de novo
synthesis of methionine, the cell will use a salvage pathway.
It will use oxaloacetate to produce homocysteine to synthesize methionine. Given that oxaloacetate and L-glutamate
are necessary to synthesize aspartate, using this salvage
pathway for the de novo synthesis of methionine, other
amino acid synthetic and catabolic pathways will be changed
within the cell (http://www.ecosal.org/ecosal/index.jsp).
Changes in other amino acid metabolic processes are
responsible for the lack of AI-3 activity in a luxS mutant.
Hence, LuxS is not involved in the synthesis of AI-3 per se
(M. Walters & V. Sperandio, unpublished results). Structural
analysis of AI-3 suggests that this signal is an aromatic
compound and does not contain a sugar skeleton like AI-2
(J.R. Falck & V. Sperandio, unpublished data).
It has recently been shown, using anaerobically cultured
stools from healthy human volunteers, that the microbial
intestinal flora produce AI-3 (Sperandio et al., 2003). To
obtain further information regarding which intestinal commensals and pathogens produce AI-3, freshly isolated strains
from patients were tested (M.P. Sircili & V. Sperandio,
unpublished observations). AI-3 activity was observed in
spent supernatants from enteropathogenic E. coli strains
from serogroups O26:H11 and O111ac:H9, Shigella sp, and
Salmonella sp. AI-3 activity was also detected in normal flora
bacteria such as commensal E. coli, Klebsiella pneumoniae,
and Enterobacter cloacae (M.P. Sircili & V. Sperandio,
unpublished observations). These results suggest that AI-3
production is not limited to EHEC and that AI-3 may be
involved in interspecies signaling among intestinal bacteria.
Besides being used in bacterial interspecies signaling, AI-3
has an intrinsic role in interkingdom communication. AI-3
cross signals with the eukaryotic hormones epinephrine/
norepinephrine in an agonistic fashion (Sperandio et al.,
2003). Both epinephrine and norepinephrine are present in
the gastrointestinal (GI) tract. Norepinephrine is synthesized within the adrenergic neurons present in the enteric
nervous system (ENS) (Furness, 2000). Although epinephrine is not synthesized in the ENS, being synthesized in the
central nervous system (CNS) and in the adrenal medulla, it
acts in a systemic manner after being released by the adrenal
medulla into the bloodstream, thereby reaching the intestine
(Purves et al., 2001). Both hormones modulate intestinal
smooth muscle contraction, submucosal blood flow, and
chloride and potassium secretion in the intestine (Horger
et al., 1998). Consequently, being able to monitor the level of
both these hormones in the intestine might aid bacteria to
gauge the metabolic state of the host. There are currently
nine known human adrenergic receptors, partitioned into
three subclasses: a1, a2, and b. Fredollino et al. (2004)recently
reported the 3D structure of human b2 adrenergic receptor,
and predicted that the ligand-binding sites for epinephrine
FEMS Microbiol Lett 254 (2006) 111

Quorum sensing: the many languages of bacteria

and norepinephrine are broadly similar. Taken together, there

is extensive evidence in the literature that both epinephrine
and norepinephrine are recognized by the same receptors,
and that both catecholamines have important biological roles
in the human GI tract. This signaling system activates
transcription of several virulence genes in EHEC.
Enterohemorrhagic E. coli O157:H7 is responsible for
major outbreaks of bloody diarrhea and hemolytic uremic
syndrome (HUS) throughout the world. EHEC has a very
low infectious dose (as few as 50 cfu), which is one of the
major contributing factors to EHEC outbreaks. Treatment
and intervention strategies for EHEC infections are still very
controversial, with conventional antibiotics usually having
little clinical effect and possibly even being harmful (by
increasing the chances of patients developing HUS (Kaper
et al., 2004)).
Enterohemorrhagic E. coli colonizes the large intestine
where it causes attaching and effacing (AE) lesions. The AE
lesion is characterized by the destruction of the microvilli
and the rearrangement of the cytoskeleton to form a
pedestal-like structure, which cups the bacteria individually.
The genes involved in the formation of the AE lesion are

encoded within a chromosomal pathogenicity island named

the LEE (Jarvis et al., 1995). The LEE region contains five
major operons: LEE1, LEE2, LEE3, tir (LEE5) and LEE4,
which encode a type III secretion system (TTSS), an adhesin
(intimin), and this adhesins receptor (Tir), which is translocated to the epithelial cell through the bacterial TTSS
(Elliott, 1998; Mellies et al., 1999). The LEE genes are
directly activated by the LEE-encoded regulator (Ler), which
is the first gene in the LEE1 operon (Mellies et al., 1999;
Elliott, 2000; Sperandio et al., 2000; Bustamante et al., 2001;
Sanchez-SanMartin et al., 2001). Transcription of the LEE
genes is further positively and negatively modulated by GrlA
and GlrR, respectively, which are encoded in a small operon
downstream of LEE1 (Deng, 2004). EHEC also produces a
potent Shiga toxin (Stx) that is responsible for the major
symptoms of hemorrhagic colitis and HUS.
Enterohemorrhagic E. coli senses AI-3 (produced by the
normal GI flora) and epinephrine/norepinephrine produced
by the host to activate expression of the LEE genes and the
flagella regulon (Sperandio et al., 2003). These signals are
sensed by sensor kinases in the membrane of EHEC that
relay this information through a complex regulatory cascade

Epinephrine/norepinephrine

AI-3

OM
IM
QseEF ATP
P

QseA

QseBC

ADP
P

flhDC

QseD

fliFGHIJK
fliA

Ler LEE1 grlRA

LEE2

LEE3

LEE5 LEE4

fliMNOPQR

fliC

fliE

motABcheWA

flgMA

tartapEcheRBYZ
Type III secretion
(AE lesion)

fliDST

Flagella and
motility

Fig. 3. Model of quorum sensing signaling in enterohemorrhagic Escherichia coli. Both AI-3 and epinephrine/norepinephrine seem to be recognized by
the same receptor, which is probably in the outer membrane of the bacteria. These signals might be imported to the periplasmic space where they
interact with two major sensor kinases. QseC might be the sensor kinase transducing these signals towards activation of the flagella regulon, whereas
QseE might be the sensor kinase transducing these signals to activate transcription of the locus of enterocyte effacement (LEE) genes. QseC
phosphorylates the QseB response regulator, which binds to the promoter of flhDC to activate expression of the flagella regulon. QseB also binds to its
own promoter to positively autoregulate its own transcription. QseE is the sensor kinase and its predicted response regulator is QseF. At what levels QseF
regulates transcription of the LEE genes remain to be established. QseA is one of the transcriptional factors involved in the regulation of ler (LEE1)
transcription in two levels, by binding and activating transcription of LEE1 and by activating transcription of the grlRA operon, where GrlA and GrlR
positively and negatively regulate expression of ler, respectively. Then, in a cascade fashion, Ler activates transcription of the other LEE genes. QseD is a
second LysR-like regulator, involved in modulating expression of the LEE and flagella genes.

FEMS Microbiol Lett 254 (2006) 111

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Published by Blackwell Publishing Ltd. All rights reserved

that activates the flagella regulon and the LEE pathogenicity

island. The sensor for the flagella regulon is QseC that
autophosphorylates in response to both epinephrine and
AI-3 and transfers its phosphate to the QseB response
regulator, which in turn activates transcription of the flagella
genes and itself (Sperandio, Torres et al., 2002; Clarke &
Sperandio, 2005a, b)(M.B. Clarke & V. Sperandio, unpublished data). We recently identified a second two-component system named QseEF, which is essential for AE lesion
formation (R. Reading & V. Sperandio, unpublished data).
Further regulation of the LEE genes is complex and requires
at least two LysR transcription factors (QseA and QseD)
(Sperandio, Li et al., 2002) (F. Sharp, M. Walters and V.
Sperandio, unpublished data), which in concert with several
global regulators in EHEC ensure the correct kinetics of LEE
gene expression (Fig. 3). The AI-3/epinephrine/norepinephrine signaling cascade is present in several bacterial
species (e.g. Shigella, Salmonella, Erwinia carotovora, Pasteurella multocida, Haemophilus influenzae, Actinobacillus
pleuropneumoniae, Chromobacterium violaceum, Coxiella
burnetti, Yersinia, Francisella tularensis and Ralstonia solacearum) suggesting that this interkingdom crosssignaling is
not restricted to E. coli.

Acknowledgements
Work in the VS laboratory was supported by NIH grants
AI053067 and AI054468, and the Ellison Foundation.

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