cell cell communication in food related bacteria cell–cell communication in food... · fish...

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obiology 120 (2007) 34–45www.elsevier.com/locate/ijfoodmicro

International Journal of Food Micr

Cell–cell communication in food related bacteria

M. Gobbetti ⁎, M. De Angelis, R. Di Cagno, F. Minervini, A. Limitone

Dipartimento di Protezione delle Piante e Microbiologia Applicata, Università degli Studi di Bari, Bari, Italy

Abstract

Although the study of quorum sensing is relatively recent, it has been well established that bacteria produce, release, detect and respond tosmall signalling hormone-like molecules called “autoinducers”. When a critical threshold concentration of the signal molecule is achieved,bacteria detect its presence and initiate a signalling cascade resulting in changes of target gene expression. Cell–cell communication has beenshown within and between species with mechanisms substantially different in Gram-positive and Gram-negative bacteria. The identified quorum-sensing mechanisms in several food related Gram-negative and Gram-positive bacteria, including bacteriocin synthesis, luxS quorum sensing andinteractions between sourdough starter lactic acid bacteria are reviewed. The understanding of extracellular signalling may provide a new basis forcontrolling over molecular and cellular process the deleterious and useful food related bacteria whose behaviour is mostly a consequence of verycomplex community interactions.© 2007 Elsevier B.V. All rights reserved.

Keywords: Quorum sensing; Cell–cell communication; Autoinducers; LuxS; Food related bacteria

1. Introduction

Bacteria were for long time believed to exist as individualcells primarily seeking to find nutrients and to multiply.Nevertheless, bacteria conduct very often an efficient censusof their population, and sense the environment, hosts andcompetitors (Fuqua et al., 1996). In such contexts bacteriaproduce, release, detect and respond to small signallinghormone-like molecules, called “autoinducers”. These signal-ling molecules accumulate and trigger cascade events when a“quorum” (e.g., a certain threshold concentration) is reached;hence the name of “quorum sensing” to describe this mechanismof cell–cell communication. The discovery of cell–cellcommunication among bacteria has led to the realization thatbacteria are capable of coordinated activity that was oncebelieved to be restricted to multicellular organisms. The term“sociomicrobiology” has also been recently introduced, mean-ing investigations of any group-behaviours of microbes (Parsek

⁎ Corresponding author. Dipartimento di Protezione delle Piante e Micro-biologia Applicata, Via G. Amendola 165/a., 70126 Bari, Italy. Tel.: +390805442949; fax: +39 0805442911.

E-mail address: [email protected] (M. Gobbetti).

0168-1605/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.ijfoodmicro.2007.06.012

and Greenberg, 2005). The capacity to behave collectively as agroup has obvious advantages, for example, the ability tomigrate to a more suitable environment/better nutrient supplyand to adopt new modes of growth, which may afford protectionfrom deleterious environments (de Kievit and Iglewski, 2000).

Quorum sensing may regulate bioluminescence (Miller andBassler, 2001), biofilm formation (Zhu and Mekalanos, 2003),competence development and sporulation (Rudner et al., 1991;Perego and Hoch, 1996), antibiotic synthesis (Takano et al.,2001; Derzelle et al., 2002), virulence factor induction in plants(Dow et al., 2003) or human (Qin et al., 2001; Bassler, 2002)host infection, bacteriocin synthesis (Eijsink et al., 1996;Brurberg et al., 1997; Quadri et al., 1997; Hauge et al., 1998),cell differentiation and nutrient flux along with other physio-logical events in bacteria (March and Bentley, 2004). Bacteriause quorum sensing to communicate either within or betweenspecies with mechanisms substantially different in Gram-positive and Gram-negative bacteria.

This review aims at describing some of the identifiedquorum-sensing mechanisms in food related Gram-negative andGram-positive bacteria, highlighting the major differences andthe new insights that probably open new genomic andproteomic perspectives for studying and monitoring microbialcommunities.

mailto:[email protected]

http://dx.doi.org/10.1016/j.ijfoodmicro.2007.06.012

35M. Gobbetti et al. / International Journal of Food Microbiology 120 (2007) 34–45

2. Quorum sensing in Gram-negative bacteria

The mechanism of quorum sensing was first described inVibrio fischeri, a bioluminescent bacterium living as a symbiontin specialized light organs of the squid Euprymna scolopes andfish Monocentris japonicus (Miller and Bassler, 2001). A briefdescription of this system is first given to compare the otherbacterial mechanisms (Fig. 1). The luxI gene, enclosed in theoperon luxICDABE, encodes for an autoinducer synthase thatsynthesizes the autoinducer N-(3-oxohexanoyl)-homoserinelactone (OHHL). LuxR encodes a transcription factor that,after interacting with the autoinducer, binds upstream of theluxICDABE operon, enabling transcription of all the necessarycomponents of the luciferase system as well as the exponentialincrease in LuxI synthesis. The LuxR transcriptor requireschaperonines GroEL and GroESL for folding into an activeconformation (Adar et al., 1992). Overall, autoinducer commu-nicates to the bacteria that they exist inside a light organ asopposed to outside in the ocean, where it would diffuse awayand never accumulate.

The general paradigma is that species-specific quorumsensing in Gram-negative bacteria is mediated by acyl-homoserine lactones (AHLs) (Fuqua et al., 2001). S-adenosyl-methionine (SAM) and acyl–acyl carrier protein (acyl–ACP)are the substrates for AHL synthesis. LuxI promotes theformation of an amide bond from the acyl–ACP to SAM (Moreet al., 1996). Lactonization of the ligated intermediate with theconcomitant release of methylthioadenosine (MTA) results in

Fig. 1. Quorum sensing in Vibrio fischeri. LuxI, autoinducer synthase; OHHL, Nencoding LuxR; and luxICDABE, luciferase structural operon. For the quorum-sens

AHL. The homoserine lactone ring is conserved in all signalsidentified (Parsek and Greenberg, 2005). AHL molecules maycontain 4- to 14-carbon acyl side chains and, at the third carbon,either an oxo, or a hydroxyl, or no substitution (de Kievit andIglewski, 2000). Cell membrane is permeable to AHL, and thus,this molecule is secreted outside the cell and accumulates in thesurrounding environment. At low cell densities, AHL passivelydiffuses out of cells down a concentration gradient, while athigh cell densities, AHL accumulates at an intracellularconcentration (ca. 10 nM) equivalent to the extracellular level(Kaplan and Greenberg, 1985). Table 1 lists the food relatedbacterial species known to possess LuxI proteins, the structuresof the autoinducers and the regulated functions.

Quorum sensing in the opportunistic pathogen and occa-sionally food related Pseudomonas aeruginosa is controlled bya hierarchical quorum-sensing circuit (de Kievit and Iglewski,2000) (Fig. 2). Specifically, two pairs of LuxI/LuxR homo-logues have been identified as LasI/LasR and RhlI/RhlR. LasIand RhlI are autoinducer synthases that produce the AHLsignals N-(3-oxododecanoyl)-homoserine lactone and N-(butyryl)-homoserine lactone, respectively (Pearson et al.,1995). These two quorum-sensing systems function in tandemto control virulence in P. aeruginosa (Pesci and Iglewski,1997). A third autoinducer has been further identified; that isnot an AHL, but 2-heptyl-3-hydroxy-4-quinolone (Pesci et al.,1999). Although most of the studies have concerned the effectof quorum sensing in the regulation of virulence factors, itappeared evident that 6 to 10% of the chromosomal genes of

-(3-oxohexanoyl)-homoserine lactone; LuxR, transcription factor; luxR, geneing mechanism see the text. Adapted from March and Bentley (2004).

Table 1LuxI/LuxR-like quorum-sensing systems in some food related Gram-negative bacteria: regulatory proteins, autoinducer identity, and target genes and functions

Organism Regulatory proteins Autoinducer identity Target genes and functions References

Vibrio fischeri LuxI/LuxR N-(3-oxohexanoyl)-HSL a luxICDABE (bioluminescence) Engebrecht et al. (1983)Burkholderia cepacia CepI/CepR N-octanoyl-HSL Protease and siderophore production Lewenza et al. (1999)Enterobacter agglomerans EagI/EagR N-(3-oxohexanoyl)-HSL Unknown Swift et al. (1993)Erwinia carotovora ExpI/ExpR N-(3-oxohexanoyl)-HSL Exo-enzyme synthesis Pirhonen et al. (1993);

Jones et al. (1993)CarR/CarI Carbapenem antibiotic synthesis Bainton et al. (1992)

Escherichia coli ?/SdiA ? ftsQAZ (cell division) chromosomereplication

Withers and Nordstrom(1998)

Pseudomonas aureofaciens PhrI/PhrR N-hexanoyl-HSL phz (phenazine antibiotic biosynthesis) Wood et al. (1997)Pseudomonas aeruginosa (1) LasI/LasR (1) N-(3-oxododecanoyl)-HSL (1) lasA, lasB, aprA, toxA (exoprotease

virulence factors) biofilm formation(1) de Kievit and Iglewski(2000)

(2) RhlI/RhlR (2) N-butyryl-HSL (2) lasB, rhlAB (Rhamnolipid),rpoS (stationary phase)

(2) Pearson et al. (1995);de Kievit and Iglewski 2000

Ralstonia solanacearum SolI/SolR N-hexanoyl-HSL N-octanoyl-HSL Unknown Flavier et al. (1997)Salmonella entericaserovar typhimurium

?/SdiA ? rck (resistance to competence killing)ORF on Salmonella virulence plasmid

Ahmer et al. (1998)

Serratia liquefaciens SwrI/? N-butanoyl-HSL Swarmer cell differentiation exoprotease Eberl et al. (1996); Givskovet al. (1997)

Yersinia enterocolitica YenI/YenR N-hexanoyl-HSL,N-(3-oxohexanoyl)-HSL

Unknown Throup et al. (1995)

Adapted from Bassler and Miller (2006).a HSL = homoserine lactone.

36 M. Gobbetti et al. / International Journal of Food Microbiology 120 (2007) 34–45

P. aeruginosa are regulated by AHLs (Arevalo-Ferro et al.,2003) and that other Pseudomonas species (e.g. Pseudomonasfluorescens) use almost the same system.

Erwinia carotovora is a phytopathogen that causes soft rot ina variety of plant products by tissue-degrading enzymes such aspectate lyases, polygalacturonase, cellulase and protease.Synthesis of these enzymes by only a few cells would nothave an effect on plant tissue, and it would activate the plantphytodefense mechanisms. Therefore, E. carotovora usesquorum sensing, which ensures that enzyme production doesnot occur until sufficient bacterial numbers are achieved (Joneset al., 1993; Pirhonen et al., 1993). This regulation relies on theLuxI/LuxR homologues ExpR/ExpI. An expImutant was foundto be deficient in exoenzyme synthesis and unable to macerateplant tissue. In contrast, the mutation of expR did not affectenzyme production, and over-expression of the expR resulted indecreased enzyme production (McGowan et al., 1995). Thissuggested that ExpR may act as a repressor of enzyme synthesisby sequestering the level of AHL. A second quorum sensingregulates the synthesis of the antibiotic carbapenem in E.carotovora. Carbapenem production is regulated by CarR/CarI;the latter catalyzes the synthesis of AHL (McGowan et al.,1995). When sufficient AHL is present, it binds to and activatesCarR, enabling it to induce expression of the carbapenembiosynthetic genes. Since the release of nutrient-rich constitu-ents from the plant promotes the growth of competingmicroorganisms, it appears that E. carotovora has developed asophisticated strategy to counteract this competition bycoordinating production of carbapenem with the tissue-macerating enzymes.

Escherichia coli and Salmonella enterica seem to have anincomplete LuxI/LuxR set of quorum sensing with respect tothe other Gram-negative bacteria (Ahmer, 2004). SdiA is the

sole LuxR-type receptor in E. coli and S. enterica, while no luxIhomologues, or any other type of AHL synthase, are found inthe complete genome sequence. SdiA has also been consideredas an example of a bacterial receptor that detects signals of othermicrobial species.

Exceptions to the LuxI/LuxR and AHL paradigma arelargely found. Genomic data indicates the presence of putativesignalling peptides (Michiels et al., 2001), cyclic dipeptides(Holden et al., 1999) and transporters in Gram-negativebacteria. One system using a protease to release a signallingpeptide was discovered in Providencia spp. and uncharacterizedhomologues were found in E. coli and S. enterica (Ahmer,2004). Studies on the effect of stationary-phase signals on thegene expression of early exponential-phase cells of E. coli,performed by the use of DNA microarrays, suggested theinvolvement of indole in the induction of tnaA and tnaL and ofphosphate in the repression of phoA, phoB and phoU genes(Ren et al., 2004). The 3-hydroxypalmitic acid methyl-esterseems to be involved in virulence regulation of Ralstoniasolanacearum, a soil-borne phytopathogen causing wiltingdiseases of many important crops (Flavier et al., 1997). Butyro-lactones have been isolated from Pseudomonas aureofaciensculture supernatants (Gamard et al., 1997) and diketopiper-azines were discovered in P. fluorescens, Pseudomonasalcaligenes and Enterobacter agglomerans (Holden et al.,1999).

3. Quorum sensing and meat spoilage by Gram-negativebacteria

The microbiota of aerobically-packed meat stored at chilltemperatures is dominated by Pseudomonas spp. (109 cfu/g atthe point of spoilage) (Lambropoulou et al., 1996) as well as

Fig. 2. Hierarchical quorum sensing in Pseudomonas aeruginosa. LasI, autoinducer synthase homologous to LuxI; AHL12, N-(3-oxododecanoyl)-homoserine lactone;LasR, transcription factor homologous to LuxR; RhlI, autoinducer synthase homologous to LuxI; AHL4, N-(butyryl)-homoserine lactone; RhlR, transcription factorhomologous to LuxR; and rhlR, gene encoding RhlR. For the quorum-sensing mechanism see the text. Adapted from Bassler and Miller (2006).


Enterobacteriaceae (105 to 107 cfu/g) represent a consistentpart of the microbiota of vacuum-packed meat together withlactic acid bacteria (Borch et al., 1996). Several authors (Gramet al., 1999; Jay et al., 2003; Bruhn et al., 2004; Medina-Martínez et al., 2006) have found the presence of AHLmolecules in commercially produced meat samples. It washypothesized that Pseudomonas spp. possess the capacity toform biofilms in fresh spoiled meats and that quorum sensing isinvolved in the overall biofilm forming and functioningprocesses (Jay et al., 2003). Since AHL-based communicationsystems regulate the expression of hydrolytic enzymes,biosurfactant production and mediate bacterial processes suchas surface motility and colonization, it was also hypothesizedthat AHL molecules could enable Enterobacteriaceae to boostthe production of enzyme system at certain cell densities,thereby contributing to quality changes at relatively low cellnumbers (Gram et al., 1999). Indeed, AHL molecules weredetectable already when cell counts reached 106 cfu/g (Bruhnet al., 2004). Overall, Hafnia alvei and Serratia spp. dominatethe Enterobacteriaceae community in vacuum-packed spoiledmeat (Borch et al., 1996; Riddel and Korkeala, 1997). Thin-layer chromatographic profiles of supernatants from severalisolates of H. alvei and Serratia spp. revealed that N-3-oxohexanoyl homoserine lactone (OHHL) was the most

frequent AHL molecule released (Bruhn et al., 2004). Althoughlargely influenced by the food ecosystem conditions, Yersiniaenterocolitica has also been found to synthesise AHL moleculessuch as OHHL and N-hexanoyl homoserine lactone in fish andmeat extracts (Medina-Martínez et al., 2006). Based on theabove findings, the application of new food preservatives suchas quorum-sensing inhibitors (Givskov et al., 1996; Hentzer etal., 2003), which specifically block the AHL regulation, wassuggested to enhance the shelf life of meat and fish products.Nevertheless, some other authors (Bruhn et al., 2004) concludedthat even though compounds inducing quorum system arecommon in spoiling vacuum-packed meat, these compounds arenot essential to the meat spoilage but may influence the spoilageof other types of foods.

4. Quorum sensing in Gram-positive bacteria

The signalling molecules, the mechanism of their synthesisand the secretion and detection apparatus used by Gram-positive bacteria differ from those of Gram-negative bacteria(Table 2). Gram-positive bacteria use a ribosomally-generatedoligopeptide called autoinducing peptide (AIP, or peptidepheromone) as communication signal. The gene for AIP oftenflanks a two-component regulatory system (2CRS) gene

Table 2Quorum-sensing systems in some food related Gram-positive bacteria: signalling molecules and functions

Organism Signalling molecules Functions References

Bacillus subtilis ComX, CSF subtilin Competence/sporulation lantibiotic synthesis Bassler and Miller (2006);Gutowski-Eckel et al. (1994)

Carnobacteriummaltaromaticum

AMP-like peptide pheromone (CS) Class II bacteriocin synthesis Rohde and Quadri (2006)

Carnobacteriumpiscicola

AMP-like peptide pheromones (CbnS,CbaX)

Class II bacteriocin synthesis Quadri et al. (1997); Kleerebezemand Quadri (2001)

Enterococcusfaecalis

GBAP, FsrB, CyIL AMP-like peptidepheromone (EntF)

Virulence Class II bacteriocin synthesis Lyon and Muir (2003);Kleerebezem and Quadri (2001)

Lactobacillusplantarum

LamD558 AMP-like peptide pheromone(PlnA)

Exo-polysaccharides synthesis, cell membrane proteinsClass II bacteriocin synthesis

Sturme et al. (2005); Diep et al.(1996); Kleerebezem and Quadri (2001)

Lactobacillussakei

AMP-like peptide pheromone (SppIP) Class II bacteriocin synthesis Eijsink et al. (1996); Kleerebezem andQuadri (2001)

Lactococcus lactis Nisin Lantibiotic synthesis Kleerebezem and Quadri (2001)Staphylococccusaureus

AIP, AgrD (agr system) Virulence Ji et al. (1997)

Streptococcuspneumoniae

CSP, BlpC Virulence, competence Lyon and Muir (2003)


cassette (Nakayama et al., 2001). The system that includes AIPin addition to 2CRS is termed three-component regulatorysystem (3CRS). The 2CRS, consisting of a membrane histidineprotein kinase (HPK) and a response regulator (RR), is themajor tool for signal transduction across cell membranes inbacteria (Hellingwerf et al., 1998). HPK and RR containcharacteristic domains, termed transmitters and receivers,respectively. In the simplest circuit, HPK contains a C-terminaltransmitter module preceded by an N-terminal signal-input (orsensor) domain with an invariant autophosphorylated histidine.RR contains an N-terminal receiver module followed by a C-terminal signal-output domain with an invariant aspartateresidue located at the centre (Stock et al., 1995). In the processof 3CRS, AIP secreted by a dedicated ATP-binding-cassetteaccumulates outside the cell and when its concentration reachesthe quorum, AIP triggers HPK by binding to its N-terminalsensor domain. The HPK transfers the phosphate group from itsown histidine to the aspartate in the signal output domain of RR,in what is called His–Asp phosphorelay. Finally, the phosphor-ylated RR activates gene transcription. Contrarily to AHLmolecules which diffuse freely across the outer and innermembranes, requiring an internalization to trigger thecorresponding response, the peptide-pheromone model doesnot include this step, because the sensor protein involved islocated on the outer surface of the cytoplasmic membrane. Avariety of phenotypes are controlled by 3CRS: synthesis ofbacteriocins in Carnobacterium piscicola (Quadri et al., 1997),Lactobacillus sakei (Eijsink et al., 1996; Brurberg et al., 1997),Lactobacillus plantarum, and Enterococcus feacium (O'Keeffeet al., 1999); conjugal transfer of plasmids in Enterococcusfaecalis (Clewell, 1993); genetic competence in Streptococcuspneumoniae (Morrison, 1997) and Bacillus subtilis (Magnusonet al., 1994); sporulation in B. subtilis (Rudner et al., 1991);expression of virulence factors in staphylococci (Novick et al.,1995); biofilm formation; and stress responses (Hoch, 2000).All available Streptococcus thermophilus genome sequences(LMG18311, CNRZ1066, and LMD9) encode eight complete

and potentially functional 2CRS with typical HPK and RRlinked genetic organization (Hols et al., 2005). Degenerateprimers were designed from consensus amino acid sequences inthe HPK10 protein subfamily, mostly involved in quorumsensing. Deduced amino acid sequences for several Lactoba-cillus, Enterococcus and Clostridium species were similar tothose of members of the HPK10 (Nakayama et al., 2003).Complete genes for the putative gene cassette were cloned byinverse PCR from Lactobacillus paracasei and L. plantarum.Phylogenetic analysis grouped the cloned putative HPKs intothe HPK10 subfamily.

It has been shown that, during Staphylococcus aureusinfection, a temporal gene expression takes place, due to twopleiotropic regulator loci called agr and sar. In fact, duringearly stage of infection, surface proteins involved in attachment(e.g.: fibronectin-binding protein) predominate, whereas, once ahigh cell density is achieved, expression of these proteins isdecreased (de Kievit and Iglewski, 2000). The agr locus of S.aureus consists of two divergently transcribed operons, RNAIIand RNAIII (Ji et al., 1997) (Fig. 3). The RNAII operoncontains the agrBDCA genes that encodes the signal transducer(AgrC) and the response regulator (AgrA). The RNAIII operonencodes a δ-hemolisin and is itself a regulatory RNA that playsa key role in the agr response. During S. aureus quorumsensing, a small (b10 amino acids) extracellular AIP from adedicated propeptide (AgrD) is secreted and accumulates. Uponreaching a threshold concentration (ca. 10 nM), the AIP binds toand triggers activation of the AgrC signal transducer whichautophosphorylates and, in turn, leads to the phosphorylation ofthe AgrA response regulator (Lina et al., 1998). PhosphorylatedAgrA stimulates transcription of RNAIII and RNAIII, in turn,up-regulates expression of numerous exoproteins as well as theagrBDCA locus (Ji et al., 1997). The latter leads to a rapidincrease in the synthesis and export of AIP. At the secondregulatory locus, the sar gene product (SarA) functions as aregulatory DNA-binding protein to induce expression of boththe RNAII and RNAIII operons (Rechtin et al., 1999). The agr

Fig. 3. Quorum sensing in Staphylococcus aureus. One operon (agrBDCA) encodes the proteins responsible for generating and sensing the peptide signal molecule(AgrD) and the other encodes δ-hemolysin and RNAIII. AgrB, membrane-associated protein; AgrC, transmembrane associated signal transducer; AgrA, responseregulator; and SarA, DNA-binding protein. For the quorum-sensing mechanism see the text. Adapted from de Kievit and Iglewski (2000).


quorum-sensing system in S. aureus represses several surfaceproteins, including fibrinogem- and fibrinectin-binding pro-teins, that mediate contact with the host matrix (Yarwood andSchlievert, 2003). Under certain conditions, agr mutants adheremore efficiently than wild-type strains to both biological andabiotic surfaces (Beenken et al., 2003).

Analogous to the agr system in S. aureus, there exists onesimilar 3CRS in E. faecalis, known as the E. faecalis regulatorfsr (Qin et al., 2001). This locus includes a HPK, FsrC, a RR,FsrA, and a putative AgrB-like processing enzyme, FsrB. Allgenes in the fsr operon are important for the production ofvirulence factors. In contrast with the agr system, where theAIP is released from the propeptide AgrD, the E. faecalis AIP islikely derived from the C terminus of the putative processingenzyme, FsrB. Another quorum-sensing circuit has beendetected in clinical isolates of E. faecalis producing theexotoxin called cytolysin. The products of two genes, cylR1and cylR2, which lack homologues of known function, worktogether to repress transcription of cytolysin genes. Derepres-sion occurs at specific cell density when one of the cytolysinsubunits reaches extracellular threshold concentration (Wolf-gang et al., 2002).

The locus of the L. plantarum WCFS1 genome that showedhomology to the staphylococcal agr quorum-sensing systemwas analysed and designated as lam for Lactobacillus agr-likemodule (Sturme et al., 2005). Analysis of a response regulator-defective mutant (ΔlamA) in an adherence assay showed thatlam regulates adherence of L. plantarum to a glass surface.The microarray analysis confirmed that lamBDCA is auto-regulatory and showed that lamA is involved in expression ofgenes encoding surface polysaccarides, cell membrane proteinsand sugar utilization proteins. A cyclic thiolactone pentapeptidethat possesses a ring structure similar to that of AIP of the

staphylococcal agr system was identified and designated asLamD558.

In B. subtilis, the quorum response is regulated by con-vergent pathways and it is mediated by a secreted 10-amino acidmodified peptide (ComX pheromone) that activates a HPK(ComP) that, in turn, activates a RR (ComA). CSF (derivedfrom the phrC gene product) also stimulates ComA activity.CSF is imported into the cells by oligopeptide permease andinhibits RapC which negatively regulates ComA. Expression ofover 20 genes appears to be controlled directly by this signallingpathway, and expression of over 150 additional genes, includingthose involved in competence development, appears to becontrolled indirectly. The genes affected appear to regulate andenhance survival, growth and colonization under conditions ofcrowding (Comella and Grossman, 2005).

Exceptions to 3CRS were also found. Small signallingmolecules, known as γ-butyrolactones, structurally similar toGram-negative AHL, that appear to function in a cell density-dependent manner to elicit antibiotic production, were foundwithin the genus Streptomyces (Takano et al., 2001).

5. Quorum sensing and bacteriocin production

Many Gram-positive bacteria, especially lactic acid bacteria,secrete small antimicrobial peptides (AMPs) which areregulated by quorum-sensing mechanisms (Klaenhammer,1993).

Lantibiotics or class I AMPs are heat-stable, post-transla-tionally modified peptides. The lantibiotic most extensivelystudied and used in food processing is nisin, synthesized byLactococcus lactis. Nisin is produced as a 57-residue precursor,containing a 23-residue N-terminal extension called leaderpeptide, that is absent in the mature molecule (de Vos et al.,


1991). The biosynthesis of nisin is encoded by the gene clusternisABTCIPRKFEG (Kleerebezem and Quadri, 2001). Besidesthe structural, processing and producer-immunity genes, thecluster contains the elements of the 2CRS system, RR (nisR)and HPK (nisK), which are involved in the regulation of nisinbiosynthesis (Fig. 4). During growth, nisin synthesis starts atearly- to mid-logarithmic phase and increases to a maximalproduction level in the early stationary phase when the highestcell density is reached. Introduction of a 4 bp deletion in thestructural nisA gene (ΔnisA) of a Lc. lactis strain that normallyproduces nisin, resulted not only in the loss of nisin productionbut also in abolition of nisA transcription. The transcription ofΔnisA was restored by the addition of sub-inhibitory amountsof nisin (Kuipers et al., 1995). Therefore, besides its function asAMP, nisin also acts as a secreted signal molecule that inducesthe transcription of the genes involved in its biosynthesis. Thesignal transduction for this process is mediated by NisK andNisR. A similar quorum-sensing mechanism was found for thelantibiotic subtilin of B. subtilis that contains genes encodingHPK (spaK) and RR (spaR) (Gutowski-Eckel et al., 1994).Based on genome sequences, the 2CRS (TCS04) of S. ther-mophilus also displays high homology with SpaK/SpaR andNisK/NisR (Hols et al., 2005). Biological relevance for thisgeneral regulatory mechanism is deduced by several factors: (i)it ensures that the concentration of the AMP in the environmentrapidly reaches a level sufficient to kill competitors; (ii) therapid increase of AMP levels through massive production athigh cell densities prevents development of immunity mechan-isms in target cells; and (iii) it protects producing cells fromineffective high level production of the AMP when growthconditions are such that the peptide pheromone rapidly diffuses

Fig. 4. Quorum-sensing regulation of class I antimicrobial peptides (AMP) in lacticproteins involved in the intracellular post-translational modification reactions; NisTprotease for removing the leader peptide; AI, autoinducer; NisK, transmembrane assexporter system that generates immunity through active cell extrusion from the cellsensing mechanism see the text. Adapted from Quadri (2002).

away from the cellular environment (Kleerebezem and Quadri,2001).

Class II AMPs are small, heat-stable antimicrobial peptidesthat do not contain modified amino acid residues. Class IIAMPs are synthesized as precursor peptides that contain an N-terminal extension that is removed during or shortly aftersecretion of the peptide. The pro-peptides of class II AMPsshare a common feature in that two glycine residues precede thecleavage site (Gly-Gly motif). In recent years, the production ofseveral AMPs of class II has been shown to be an induciblerather than a constitutive phenotype (Kleerebezem and Quadri,2001). Synthesis of carnobacteriocin A, B2 and BM1 by C.piscicola LV17 (Saucier et al., 1995; Quadri et al., 1997),several different putative plantaricins (PlnJK, PlnEF and PlnN)by L. plantarum C11 (Diep et al., 1995, 1996), and sakacin P byL. sakei LTH673 (Eijsink et al., 1996) was lost upon inoculationof an overnight culture of a producing (Bac+) strain into freshculture medium at a level that is lower than a certain thresholdinoculum size (varying from b106 to b104 cfu/ml). The Bac-

phenotype persisted during subsequent sub-cultivation in aninoculum size-independent manner, but could be reversed byaddition of a small volume (varying from 0.01 to 1.0%) of cell-free Bac+ culture supernatant, indicating the presence of aninducing factor in the Bac+ culture supernatant. Except forplantaricin A and carnobacteriocins which have dual activity,the inducer peptides differ from the AMPs in that they lackantimicrobial activity and are slightly shorter. It seems likelythat inducer peptides depend on the same machinery as AMPs.Contrarily to the cell density-dependent regulatory model forGram-positive bacteria, the regulation of class II AMPproduction by lactic acid bacteria does not appear to fulfil this

acid bacteria. NisABTCIPRKFEG, gene cluster encoding nisin; NisB and NisC,, putative transport protein of the ABC translocator family; NisP, extracellularociated signal transducer; NisR, response regulator; NisF, NisE and NisG, ABC; and NisI, lipoprotein that contributes to producer-immunity. For the quorum-


requirement, which might suggest the involvement of otherenvironmental factors (Pozzi et al., 1996). It is possible that, inresponse to suboptimal or changing physiological conditions,the level of peptide-pheromone production is temporarily in-creased in order to reach the threshold level, leading to whatcould be called a growth-conditions-dependent phenotype.

6. LuxS quorum sensing

Vibrio harveyi contains an interesting blend of Gram-positive and Gram-negative quorum-sensing mechanisms(Bassler et al., 1994). Two parallel systems converge to regulateluxCDABE, the luciferase structural operon. System 1, consist-ing of autoinducer-1 (AI-1) and sensor 1 (LuxN), is involved inintraspecies quorum sensing. System 2, consisting of auto-inducer 2 (AI-2) and sensor 2 (LuxPQ), could be used forinterspecies cell–cell communication (Surette et al., 1999). AI-1[N-(4-hydroxybutyl)-L-homeserine] is a typical Gram-negativeAHL, but it signals through a typical 2CRS, like in Gram-positive bacteria. AI-2 does not resemble any other knownsignalling molecule and yet signals also through a 2CRS.

AI-2 is a furanosyl borate diester produced from SAM, anessential cofactor for DNA, RNA and protein synthesis, in atleast three enzymatic steps (Fig. 5). Two enzymes, MetF andMetE, located upstream of LuxS in the metabolic pathwayseem to be indispensable for the generation of methionine,which is part of SAM (Schauder et al., 2005). Consumption ofSAM as a methyl donor produces S-adenosylhomocysteine(SAH), which is hydrolyzed by the nucleosidase Pfs to yieldadenine and S-ribosylhomocysteine (SRH). LuxS catalyzes thecleavage of SRH to 4,5 dihydroxy-2,3-pentanedione (DPD) andhomocysteine. DPD forms a cyclic molecule and undergoes

Fig. 5. Synthesis of autoinducer AI-2 by LuxS. SAH is toxic and is removed in twoadenine, homocysteine and DPD; or one-step conversion using SAH-hydrolase (Sah

further rearrangements to yield AI-2 (Schauder et al., 2001).The proposed AI-2 structure contains two fused five-memberedrings stabilized within the LuxP binding site by numerous polarinteractions. Several candidates were considered for the atombridging the diester, being boron the most suitable (Chen et al.,2002). The other characterized structure is AI-2 of S. entericaserovar typhimurium (De Keersmaecker et al., 2006). Thebiosynthetic route to synthesize DPD has been shown to beidentical in E. coli, Vibrio cholerae, E. faecalis and S. aureus(Schauder et al., 2001; Winzer et al., 2002).

DNA database analysis revealed that highly conservedhomologues of luxS are present in over 30 species of bothGram-negative and Gram-positive bacteria, including but notlimited to E. coli, Salmonella, B. subtilis, Campylobacter jejuni,E. faecalis, Streptococcus pyogenes, S. aureus and Clostridiumperfringens (Bassler and Miller, 2006). Currently, AI-2 isconsidered a universal language that bacteria could use forinterspecies communication (De Keersmaecker et al., 2006).The phylogenetic tree of the LuxS protein was reconstructed(Lerat and Moran, 2004). The Firmicutes forms a clad separatedfrom the Proteobacteria. Inside the Proteobacteria, each division(α, β and ε) is distinct. Within the monophyletic groupFirmicutes, there are four sequences. The most surprising isthe position of the LuxS ofHelicobacter pylori as sister group toStaphylococcus, Listeria, and Bacillus species and distant fromC. jejuni. This suggests that H. pylori acquired the luxS genefrom the Firmicutes. Bifidobacterium longum was found assister group to the Firmicutes L. plantarum and Lc. lactis, andseveral Streptococcus. B. longum colonizes the human gastro-intestinal tract where it is considered an important commensal.L. plantarum and Lc. lactis are also known to be natural in-habitants of the human gastrointestinal tract. Thus, the proximity

ways, either using a two-step conversion by Pfs and LuxS enzymes, producingH). Adapted from De Keersmaecker et al. (2006).


of the habitat of these species might explain the possibility ofgene transfers among them. It is assumed that all LuxScontaining bacteria synthesize the DPD precursor. Probably,LuxS-containing bacteria release DPD or specific furanones,and then each recipient species acts on the precursor to generate aspecific AI-2 signal. Several features of the AI-2 biosyntheticpathway suggest that AI-2 harbours information about cellnumber and also the growth phase and prosperity of the cells in apopulation. First, as with any secreted molecule, extracellularAI-2 accumulation will be proportional to cell number. Second,one DPDmolecule, and possibly one AI-2molecule, is producedevery time SAM is used as a methyl donor. This intimate linkbetween SAM metabolism and AI-2 production makes AI-2 anexcellent device for measuring the metabolic potential of a cellpopulation. Third, because a lethal intermediate exists in thepathway generating AI-2, the Pfs detoxification mechanismensures that as long as a population of bacteria is growing (e.g. isusing SAM), substrate for AI-2 production will be available.Conversely, if a population is not growing (e.g., decreases theuse of SAM), AI-2 production will slow down (Xavier andBassler, 2003).

C. perfringens uses AI-2/LuxS to regulate toxin production(Ohtani et al., 2002). The timing of toxin production is criticalfor virulence in C. perfringens and occurs at mid-lateexponential growth phase. This coincides with the timing ofmaximal AI-2 production. Analysis of toxin mRNA levelsshows that, compared with the wild-type, C. perfringens luxSmutants have reduced toxin transcription at mid-log phase,whereas at stationary phase, mutant and wild type toxin mRNAlevels are similar.

LuxS of the pathogen S. enterica serovar typhimurium isrequired for biofilm formation on human gallstones (Prouty et al.,2002). LuxS controlled genes were identified inE. coli under twodifferent growth conditions using DNAmicroarrays (Wang et al.,2005). Twenty-three genes were affected by luxS deletion in thepresence of glucose, and 63 genes were influenced by luxSdeletion in the absence of glucose. Minimal overlap among thesegene sets suggests the role of luxS is condition dependent.

Two 2(5H)-furanones, chemically similar to AHL butpresumably coming from different precursors, are released byLactobacillus helveticus exposed to oxidative and heat stresses(Ndagijimana et al., 2006). Besides known autolysins, newautolysins were found in concomitance with the exposure of L.helveticus to cell-free supernatants and to 5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone. Morphological changes were alsofound under these conditions. The chemical structure of theabove furanones is different from those identified in somecheeses having L. helveticus as starter.

7. Proteomic study of sourdough lactic acid bacteria

Beyond genetic tools, proteomic studies of quorum sensinghave been already performed in E. coli (Allen et al., 2002), P.aeruginosa (Arevalo-Ferro et al., 2004), Burkholderia cenoce-pacia (Riedel et al., 2003), Rhizobium leguminosarum (Canteroet al., 2006) and Sinorhizobium meliloti (Chen et al., 2003). In arecent study (Di Cagno et al., in press) dealing with sourdough

lactic acid bacteria, the growth of the key starter bacteriumLactobacillus sanfranciscensis CB1 in mono-culture wascompared with that in co-cultures with L. plantarum DC400,Lactobacillus brevis CR13 or Lactobacillus rossiae A7.Compared to mono-colture, L. sanfranciscensis CB1 at latestationary phase over-expressed 48, 42 and 14 proteins whenco-cultured with strains DC400, CR13 and A7, as shown byproteomic analyses. Induced polypeptides, only in part commonto all co-cultures, were identified as stress proteins, energymetabolism related enzymes and proline dehydrogenase, GTP-binding protein, S-adenosyl-methyltransferase, and Hpr phos-phocarrier protein. By using primers designed from consensusamino acid sequences of phylogenetically related bacteria, twoquorum sensing involved genes, luxS and metF were shown tobe expressed in L. sanfranciscensis CB1. The phylogenetic treebased on the deduced amino acid sequence of LuxS showed thehighest similarity with Lactobacillus delbrueckii subsp. bul-garicus ATCC 11842, Lactobacillus reuteri 100–23, L. plan-tarum WCFS1 and Lactobacillus salivarius subsp. salivariusUCC118. After the stationary phase of growth was reached, theexpression of luxS gene was only found in the co-culture ofL. sanfranciscensis CB1 with L. brevis CR13. Phenotypically,the rate of dead cells, fermentation end-products and proteolyticactivities reflected the type of associations.

8. Conclusion

Since long time ago, microbiologists and bacterial geneticistshave studied bacteria and their performance mainly under pureculture and/or mono-culture model systems. It is likely that,especially for food matrix, future massive genetic and proteomicefforts have to be focused to understand cell–cell signalling,coordinated behaviour, microbial interactions and biogenesis,maintenance and function of microbial community structures.Extracellular signalling may provide a new basis for controllingover molecular and cellular process the deleterious and usefulfood related bacteria which mostly behave as a consequence ofvery complex community interactions. Besides, the recentobservations that plants and animals are able to listen toquorum-sensing conversations among bacteria andmake diverseresponses to what they hear open new and more complexapplications for the cell–cell communication mechanisms(Bauer et al., 2005).

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