Quorum sensing in Escherichia coli and Salmonella

Quorum sensing in Escherichia coli and Salmonella

ARTICLE IN PRESS International Journal of Medical Microbiology 296 (2006) 125–131 www.elsevier.de/ijmm REVIEW Quorum sensing in Escherichia coli an...

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ARTICLE IN PRESS

International Journal of Medical Microbiology 296 (2006) 125–131 www.elsevier.de/ijmm

REVIEW

Quorum sensing in Escherichia coli and Salmonella Matthew Walters, Vanessa Sperandio Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9048, USA

Abstract Quorum sensing in Escherichia coli and Salmonella has been an elusive topic for a long time. However, in the past 8 years, several research groups have demonstrated that these bacteria use several quorum-sensing systems, such as: the luxS/AI-2, AI-3/epinephrine/norepinephrine, indole, and the LuxR homolog SdiA to achieve intercellular signaling. The majority of these signaling systems are involved in interspecies communication, and the AI-3/ epinephrine/norepinephrine signaling system is also involved in interkingdom communication. Both E. coli and Salmonella reside in the human intestine, which is the largest and most complex environment in the mammalian host. The observation that these bacteria evolved quorum-sensing systems primarily involved in interspecies communication may constitute an adaptation to this environment. The gastrointestinal tract harbors a high density and diversity of bacterial cells, with the majority of the flora residing in the colon (1011–1012 bacterial cells/ml). Given the enormous number and diversity of bacteria inhabiting the gastrointestinal environment, it should not be surprising that the members of this community communicate amongst themselves and with the host itself to coordinate a variety of adaptive processes. r 2006 Elsevier GmbH. All rights reserved. Keywords: Escherichia coli; Salmonella; Quorum sensing; AI-2; AI-3

Contents SdiA quorum-sensing system . . . . . . . . . . . . . . . . . . . Indole signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . The luxS/AI-2 quorum-sensing system . . . . . . . . . . . . The AI-3/epinephrine/norepinephrine signaling system. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author. Tel.: +1 214 648 1603; fax: +1 214 648 5905. E-mail address: [email protected] (V. Sperandio).

1438-4221/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijmm.2006.01.041

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SdiA quorum-sensing system Quorum sensing was first described in the regulation of bioluminescence in Vibrio 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 N-acyl-homoserine-lactone (AHL) autoinducer and LuxR, which is activated by this autoinducer to increase transcription of the luciferase operon (Engebrecht et al., 1983; Engebrecht and Silverman, 1984). Since this initial description, homologues of LuxR–LuxI have been identified in other bacteria and in all of these LuxR–LuxI 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 (Davies et al., 1998; de Kievit and Iglewski, 2000; Parsek and Greenberg, 2000). Escherichia coli and Salmonella have a LuxR homologue, SdiA (Wang et al., 1991), but do not have a luxI gene, and do not produce AHLs (Michael et al., 2001; Swift et al., 1999). 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 multi-copy 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 cultured 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 so the effects seen could be artifacts due to 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 quorum sensing 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).

Indole signaling Indole is a diagnostic marker for the identification of E. coli and is formed from tryptophan by the

tryptophanase enzyme, encoded by the tna gene. Wang et al. (2001) have demonstrated that indole can also act as a signaling molecule, and that it activates transcription of gabT, astD and tnaAB genes. Activation of the tnaAB operon is predicted to induce more indole production. The other two targets of indole-mediated signaling, astD and gabT are involved in pathways that degrade amino acids to pyruvate or succinate. These results led Wang et al. (2001) to speculate that signaling by indole may have a role in adaptation of bacterial cells to a nutrient-poor environment where amino acid catabolism is an important energy source.

The luxS/AI-2 quorum-sensing system The most widespread quorum-sensing system is the luxS system, first described as being involved in bioluminescence in Vibrio harveyi (Surette et al., 1999). Among the diverse bacterial species that contain the luxS quorum-sensing system are E. coli and Salmonella (Surette and Bassler, 1998; Surette et al., 1999). LuxS is an enzyme involved in the metabolism of S-adenosylmethionine (SAM); it converts S-ribosyl-homocysteine into homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD). DPD is a very unstable compound that reacts with water and cyclizes to form several different furanones (Schauder et al., 2001; Sperandio et al., 2003; Winzer et al., 2002a), one of which is thought to be the precursor of autoinducer-2 (AI-2) (Schauder et al., 2001). The AI-2 structure has been solved by co-crystallizing this ligand with its receptor LuxP (a periplasmic protein that resembles the ribose-binding protein RbsB) in V. harveyi, and reported to be a furanosyl-borate-diester (Chen et al., 2002). However, LuxP homologues, as well as homologues from this signaling cascade, have only been found in Vibrio sp. Many other bacterial genera harbor the luxS gene, and have AI-2 activity as measured using a V. harveyi bioluminescence assay (Schauder and Bassler, 2001; Xavier and Bassler, 2003). However, the only genes shown to be regulated by AI-2 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, 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; Sperandio et al., 2003; Winzer

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AI-3

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LsrB

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QseBC

P-AI-2 QseA

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lsrB

lsrF lsrE lsrG

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Fig. 1. Model of quorum-sensing signaling in EHEC. Both AI-3 and epinephrine/norepinephrie 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 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, and other effector proteins encoded outside of the LEE. 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. EHEC also possess an lsr operon involved in recognition and uptake of AI-2, however the role of AI-2 signaling in EHEC remains to be addressed.

et al., 2002a). These fractions only yielded several furanones which did not contain boron. These results can be explained now that AI-2 has been co-crystallized 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 [RTHMF] (Miller et al., 2004), consistent with what has been observed in AI-2 fractions of Salmonella and E. coli (Schauder et al., 2001; Sperandio et al., 2003; Winzer et al., 2002a). 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 as a signal (Winzer et al., 2002a, b). 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. Among these roles are the LEE-encoded type III secretion system (TTSS) and flagella expression in EHEC. However, using purified and in vitro synthesized AI-2, it has been demonstrated that the signaling molecule activating type III secretion and the flagella regulon in EHEC is not the AI-2 autoinducer (Sperandio et al.,

2003). The autoinducer responsible for this signaling is dependent on the presence of the luxS gene for its synthesis in these conditions, but is different from AI-2. AI-2 is a very polar furanone that does not bind to C-18 columns. The signaling compound activating the EHEC virulence genes, which was renamed autoinducer-3 (AI-3), binds to C-18 columns and can only be eluted with methanol (Sperandio et al., 2003). Electrospray mass spectrometry analysis of the AI-3 fraction showed a major peak with a mass of 213.1 Da, and minor peaks at 109.1, 164.9, 176.1, 196.1, 211.1, 214.1 and 222.9 Da (Sperandio et al., 2003). Further structural analysis of AI-3 suggests that this signal is an aromatic compound, and does not contain a sugar skeleton like AI-2 (Sperandio, unpublished data). These results suggest that some of the phenotypes previously attributed to AI-2 signaling need to be reviewed given that 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 due to a luxS mutation will involve genes affected by quorum sensing 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

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because it is unable to catalyze its conversion to homocysteine. This 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, by 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). It is possible that changes in other amino acid metabolic processes may be responsible for the lack of AI-3 activity in a luxS mutant, and that LuxS may not be involved in the synthesis of AI-3 per se. The activity of both signals can be differentiated by utilizing biological tests specific for each signal. For example, AI-3 shows no activity for the AI-2 bioassay (Sperandio et al., 2003), which is predicated on the production of bioluminescence in V. harveyi (Surette and Bassler, 1998), and is the gold standard for AI-2 production. On the other hand, AI-3 activates the transcription of the EHEC LEE virulence genes, whereas AI-2 has no effect in this assay (Sperandio et al., 2003). 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). It has recently been shown, using anaerobically cultured stools from healthy human volunteers, that the microbial intestinal flora produce both AI-2 (using the V. harveyi bioluminescence assay) and AI-3 (using the EHEC virulence gene transcription AI-3-dependent bioassay) (Sperandio et al., 2003). To obtain further information regarding which intestinal commensals and pathogens produce AI-2 and AI-3, freshly isolated strains from patients were tested (Sircili and Sperandio, unpublished observations). Using the bioassays described above, AI-2 and 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. Activity indicative of the presence of both autoinducers was also detected in normal flora bacteria such as commensal E. coli, Klebsiella pneumoniae and Enterobacter cloacae (Sircili and Sperandio, unpublished observations). These results suggest that AI-3 production is not limited to EHEC and that both AI-2 and AI-3 may be involved in interspecies signaling among intestinal bacteria.

The AI-3/epinephrine/norepinephrine signaling system Humans have an important association with their intestinal microbial flora. The microbial flora helps to

shape the mammalian innate immune system and to absorb nutrients, and plays an intricate role on intestinal development (Hooper and Gordon, 2001). In fact, it is estimated that in humans the total microbial population within the gastrointestinal (GI) tract (ca. 1014) exceeds the total number of mammalian cells (ca. 1013) by at least an order of magnitude (Berg, 1996). Mammalian cells, as well as microbes, communicate with each other through an array of hormone and hormone-like chemical compounds. These ‘‘signals’’ however, are high-jacked by bacterial pathogens, such as EHEC, to activate virulence genes, colonize the host and initiate the disease process. EHEC O157:H7 is responsible for major outbreaks of bloody diarrhoea and hemolytic uraemic 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). EHEC 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 the chromosomal LEE pathogenicity island (Jarvis et al., 1995). The LEE region contains five major operons: LEE1, LEE2, LEE3, tir (LEE5) and LEE4, which encode a TTSS, an adhesin (intimin) and its receptor (Tir), which is translocated to the epithelial cell through the bacterial TTSS (Elliott et al., 1998; Mellies et al., 1999). The LEE genes are directly activated by the LEEencoded regulator (Ler), which is the first gene in the LEE1 operon (Bustamante et al., 2001; Elliott et al., 2000; Mellies et al., 1999; Sanchez-SanMartin et al., 2001; Sperandio et al., 2000). 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 et al., 2004). EHEC also produces a potent Shiga toxin (Stx) that is responsible for the major symptoms of hemorrhagic colitis and HUS. There are two types of Stx, Stx1 and Stx2, which are most frequently associated with human disease. Both of the genes encoding Stx1 and Stx2 are located within the late genes of a l-like bacteriophage, and are transcribed when the phage enters its lytic cycle (Neely and Friedman, 1998). Disturbances in the bacterial membrane, DNA replication or protein synthesis (which are the targets of conventional antibiotics) may trigger the SOS response in the bacterial cells that triggers the lytic cycle of the bacteriophage (Kimmitt et al., 1999, 2000). The phage replicates, Stx is produced,

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and the phage lyses the bacteria thereby releasing Stx in the host. EHEC senses two classes of signals to activate its virulence genes, the first is the bacterial aromatic autoinducer (AI-3) produced by the normal GI flora, and the second is the catecholamine class of hormones and in particular epinephrine/norepinephrine produced by the host (Sperandio et al., 2003). AI-3 and epinephrine/norepinephrine are agonists, and the response to both signals can be blocked by a and badrenergic antagonists (Sperandio et al., 2003). Norepinephrine has been previously reported to induce bacterial growth (Freestone et al., 2000), and there are reports in the literature that imply that norepinephrine might function as a siderophore (Freestone et al., 2000). Recently, norepinephrine has been implicated as inducing expression of enterobactin and iron uptake in E. coli, suggesting that this is the mechanism involved in growth induction (Burton et al., 2002). However, the role of norepinephrine in bacterial pathogenesis appears to be more complex, as several reports suggested that this catecholamine also activates virulence e.g. Stx gene expression in E. coli (Lyte et al., 1996) by an unknown mechanism of induction. Both epinephrine and norepinephrine are present in the GI tract. Norepinephrine is synthesized within the adrenergic neurons present in the enteric nervous system (Furness, 2000). Although epinephrine is not synthesized in the enteric nervous system, being synthesized in the central nervous system 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). There are currently nine known human adrenergic receptors, partitioned into three subclasses: a1, a2 and b. Freddolino et al. (2004) recently reported the 3D structure of human b2 adrenergic receptor, and predicted that the ligand-binding sites for epinephrine 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. The LEE genes and the flagella regulon are activated through the AI-3/epinephrine/norepinephrine signaling mechanism (Sperandio et al., 1999; Sperandio et al., 2001; 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 that activates the flagella regulon, and the LEE pathogenicity island, necessary for intestinal colonization through the formation of AE lesions. The sensor for the flagella regulon is QseC that autophosphorylates in response to

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both epinephrine and AI-3, transfers its phosphate to the QseB response regulator, which in turn activates transcription of the flagella genes and itself (Sperandio et al., 2002b) (Clarke and Sperandio, unpublished data). We recently identified a second two-component system named QseEF which is essential for AE lesion formation (Reading and Sperandio, unpublished data). Further regulation of the LEE genes is complex and requires at least two LysR transcription factors (QseA and QseD) (Sperandio et al., 2002a) (Sharp, Walters and Sperandio, unpublished data), which in concert with several global regulators in EHEC ensure the correct kinetics of LEE gene expression (Fig. 1). 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 cross-signaling is not restricted to E. coli.

Conclusions E. coli and Salmonella have several quorum-sensing systems. However, a complete understanding of these systems and the level of cross-signaling operating amongst these enteric bacteria is still in its infancy. Most of these systems also seem to be intrinsically involved in metabolism. Teasing out the metabolic and signaling roles of each of these systems will not be an easy task, but is crucial to our understanding of bacterial basic metabolism and cell-to-cell communication.

Acknowledgments Work in V. Sperandio’s laboratory has been supported by NIH Grants AI053067 and AI054468, and the Ellison Foundation. M. Walters was supported by NIH Training Grant 5-T32-AI007520.

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