Department of Ecology and Evolutionary Biology, University of Arizona, Tucson
Correspondence: E-mail: lerat{at}email.arizona.edu.
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Abstract |
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Key Words: quorum-sensing lateral gene transfer evolution gene duplication gene family phylogenetics
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Introduction |
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Although initially considered to be a specialized system of V. fischeri and related species, experimental work later revealed homologous systems with diverse biological roles in other proteobacterial species. These included Pseudomonas aeruginosa, a human pathogen in which two circuits act in parallel to control the expression of a number of virulence factors (Jones et al. 1993; Passador et al. 1993; Brint and Ohman 1995), Erwinia carotovora, a plant pathogen with separate QS systems for expression of enzymes that attack the host (Jones et al. 1993; Pirhonen et al. 1993) and production of antibiotics (Bainton et al. 1992), and Agrobacterium tumefaciens, a plant pathogen whose luxI/R homologs (traI/R) are located on a plasmid and control conjugal transfer of the plasmid between bacteria (Fuqua and Winans 1994). The nature of the autoinducer varies among species and among systems in the same species. Each pathway responds to its own autoinducer signal.
The characterization of further QS systems has revealed different levels of evolutionary conservatism for different autoinducer systems. For example, in the free-living marine bacterium Vibrio harveyi, the LuxI/R system is absent, and light production is controlled by two nonhomologous parallel pathways (Bassler et al. 1993; Bassler, Wright, and Silverman 1994). In one of those, the autoinducer is not an AHL, but a furanosyl borate diester (Chen et al. 2002), for which synthesis is controlled by the gene luxS, and the receptor is a membrane-associated sensor kinase, LuxQ. This inducer has been found in a large range of gram-negative and gram-positive bacteria, including some pathogens (Surette, Miller, and Bassler 1999; Miller and Bassler 2001). Because this autoinducer and its biosynthetic pathway are the same among all bacterial species that possess luxS, it has been proposed that this system could be used in interspecies communication (Mok, Wingreen, and Bassler 2003). In some species, luxS has been linked to regulatory functions, such as control of toxin production in Clostridium perfringens (Ohtani, Hayashi, and Shimizu 2002) and of the virulence cascade in Vibrio cholerae, Escherichia coli, and S. typhimurium (Surette, Miller, and Bassler 1999; Miller et al. 2002), but the role of the autoinducer remains largely unknown.
The genes underlying QS are distributed in a discontinuous manner among the bacteria (Surette, Miller, and Bassler 1999; Miller and Bassler 2001), suggesting that they have been subject to loss or horizontal transfer. In this regard, gene phylogenies for the components of QS systems can provide evidence as to whether they are ancestral and lost in some species or have been acquired from distantly related lineages. Knowledge of the evolutionary mechanisms of such genes is of particular importance because they are increasingly being considered as potential targets in new antimicrobial strategies.
Here, we present phylogenetic analyses of genes underlying the two QS systems, LuxI/R and LuxS. The genes that are regularly referred to as the LuxI/R families in fact constitute two families in each case. Although these could be very ancient paralogs, the sequence similarity is not sufficient to allow their inclusion in the same phylogenetic analysis. We use these phylogenies to address the basis for the observed distributions of QS genes in bacteria. Specifically, we examine (1) the extent to which LuxI and LuxR have coevolved versus the extent to which they have switched partners and (2) the extent to which the distributions of LuxI/R and LuxS reflect vertical transmission along the organismal phylogeny versus horizontal transmission among lineages.
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Material and Methods |
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Alignments and Phylogenies
The alignments for each group of sequences were created using the ClustalW program version 1.8 (Thompson, Higgins, and Gibson 1994) and then were corrected by hand using the SEAVIEW sequence editor (Galtier, Gouy, and Gautier 1996). The Tree-Puzzle program version 5.1 (Schmidt et al. 2002) was used to determine the alpha parameter from the data sets for the gamma-based method for correcting the heterogeneity in substitution rates among sites ( correction).
We used several methods to reconstruct phylogenies for each protein alignment: a maximum likelihood reconstruction with the JTT model of substitution (Jones, Taylor, and Thorton 1992) and the correction in the PROML module of PHYLIP version 3.6 (Felsenstein 2002); the neighbor-joining (NJ) method with 500 bootstrap replicates, the Poisson correction distance and the
correction using the MEGA program (Kumar, Tamura, and Nei 1993); the minimum-evolution method with the
correction also using the MEGA program; and the NJ method with the Poisson correction distance and with 500 bootstrap replicates implemented in the Phylo_win program (Galtier, Gouy, and Gautier 1996). We used several methods to determine the robustness of the results to artifacts. Because we obtained identical topologies from all methods, we present only those from NJ as implemented in MEGA.
The SSU rRNA tree of all species was reconstructed using the NJ method with 500 bootstrap replicates and with the correction using MEGA (Kumar, Tamura, and Nei 1993).
Our goal was to determine whether the phylogenies for each QS gene family showed overall agreement with the organismal phylogeny as reflected in the SSU rRNA tree. We wished to identify any cases in which lack of congruence clearly indicated the occurrence of lateral gene transfers (LGT) in particular lineages. We did not perform statistical tests of congruence between the SSU rRNA tree and the different trees obtained from the protein alignments, because detection of significant conflict could be explained through several processes, including LGT in any of the lineages.
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Results and Discussion |
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The first family (family A) grouped Proteobacteria from different divisions (, ß, and
), whereas family B contained only
-Proteobacteria. One interpretation is that family B has arisen relatively recently within the
-Proteobacteria. The most likely timing for this origin is after the divergence of Xanthomonas species and Xylella, which lack homologs (Bhattacharyya et al. 2002), but before the divergence from Pseudomonas species, which do contain homologs of these genes.
The existence of two families in the LuxI/R alignments raises questions about their differences in function or structure, despite involvement in similar processes. Investigations of the molecular aspects of the activation and the binding of the receptor proteins (Qin et al. 2000) have shown that the TraR protein of A. tumefaciens exists in a monomer form without the presence of the inducer. The binding of the AHL induces the formation of a stable homodimer that binds the promoter of the target genes to activate their transcription (Qin et al. 2000). Such a mechanism is also found for LuxR in V. fischeri and LasR in P. aeruginosa; in the latter case, there is even multimerization after fixation of the signal molecule (Kiratisin, Tucker, and Passador 2002). All of these proteins are members of family A. In contrast, members of family B, CarR and ExpR in E. carotovora and EsaR in Erwinia stewartii, have been shown to dimerize and to bind to the promoter sequences in absence of the inducer (Welch et al. 2000). In the case of EsaR, it has been demonstrated that the protein acts as a repressor rather than as a transcription activator in the presence of the inducer molecule (Minogue et al. 2002). This difference in mechanism of regulation suggests that the two families might have diverged in the very ancient past. Further investigations will be needed to determine if differences in mechanism apply to all proteins of each family. Already one counterexample exists. In P. aeruginosa, the RhlI/R system belongs to family A but exists in the cell as a homodimer in absence of signal (Ventre et al. 2003).
We failed to find a correlation between gene family and a particular type of AHL, the phenotype expressed by the QS system, or the environment of the bacterium. This lack of pattern may be a result of the lack of information for many species. The discovery of homologs from the two families in other species may give more insight into the evolutionary lability of particular QS systems.
Evolution of LuxI/R Family A
Tree Reconstruction
Figures 1A and B show the tree reconstructions of the LuxI and LuxR proteins for family A. As the different methods led to identical topologies, only the NJ trees obtained in MEGA are represented.
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Both of the groups formed by the inducers RhlI, CsaI, and PhzI in Pseudomonas and their corresponding receptors (RhlR, CsaR, and PhzR) show a close relationship to genes of the ß-proteobacterial species.
This group of receptors is closely related to the SdiA (for suppressor of cell division inhibitor) proteins, which are known to play a variety of roles in enterobacteria, including the regulation of cell division by the activation of the ftsQAZ operon (Wang, de Boer, and Rothfield 1991), and the expression of virulence genes (Ahmer et al. 1998; Kanamaru et al. 2000). The species possessing SdiA do not have a corresponding inducer and are therefore unable to produce an AHL. In S. typhimurium, it was shown that SdiA can detect AHL produced by other bacterial species (Smith and Ahmer 2003), suggesting that this protein could be involved in recognizing the presence of foreign bacteria.
The only clear-cut incongruence between the two trees involves the BviR protein of Burkholderia cepacia (ß-Proteobacteria), which groups with the PhzR protein of P. aeruginosa (-Proteobacteria), suggesting a replacement of the receptor in B. cepacia. Whereas BviI probably underlies production of the inducer for BviR in B. cepacia, no corresponding inducer gene for PhzR seems to be present in the complete genome of P. aeruginosa. Interestingly, these two human pathogens occasionally coinfect the same individual and have been demonstrated to be able to communicate and coordinately regulate virulence factors (Lewenza, Visser, and Sokol 2002).
Gene Duplications and Acquisitions
Although the LuxI and LuxR trees are globally congruent, indicating fidelity of the inducer and receptor genes to one another, it is still possible that they have been transferred as a pair between different organisms, and this possibility is strengthened by the fact that they often occur in tandem on the bacterial chromosome (Gray and Garey 2001). Using the SSU rRNA tree to represent the organismal phylogeny, the LuxI and LuxR family A trees show substantial agreement with the SSU rRNA tree (fig. 2). Besides the case of B. cepacia discussed above, both ß-proteobacterial and -proteobacterial genes are monophyletic. In contrast, genes from the
-Proteobacteria are paraphyletic, and they are also the only group in which homologs are found within a single genome. In the case of Pseudomonas chlororaphis and P. fluorescens, pairs of paralogs (RhlI and PhzI in P. fluorescens and CsaI and PhzI in P. chlororaphis) appear to have arisen from a duplication in the ancestral genome of these two species, followed by speciation. The same pattern is seen for the receptor genes, providing a clear case of parallel evolution for the receptor and the inducer genes. Interestingly, PhzI/R in P. chlororaphis and P. fluorescens regulate the same gene expression: they are implicated in the production of phenazine antibiotics (Mavrodi et al. 1998). However, the two other orthologs, CsaI/R and RhlI/R, do not have homologous functions. In P. fluorescens, RhlI/R regulate the expression of antifungal products (Flavier et al., personal communication), and, in P. chlororaphis, CsaI/R are implicated in the biosynthesis of cell surface components (Zhang and Pierson 2001).
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Evolution of LuxI/R Family B
Tree Reconstruction
The phylogenies reconstructed for the members of family B (figs. 1C and D) display globally similar topologies, with the position of the inducer mirroring that of the corresponding receptor. (Because the different methods led to identical topologies, only the NJ trees obtained in MEGA are presented.) Three groups appear in the two trees.
The first group contains sequences of Yersinia, Pantoea, Serratia, and Hafnia. The second group contains sequences from Yersinia, Erwinia, and Serratia. The third group encompasses Pseudomonas sequences. One explanation for these groupings is that the first two groups correspond to paralogs originating from duplications that occurred after the divergence from Pseudomonas but before the speciation of all the other organisms; this explanation would imply a large number of independent losses.
The principal strongly supported difference between the two trees concerns the position in a basal part of the tree of the CarR proteins of Serratia marcescens and E. carotovora, which form a sister group quite distinct from their paralogs. This could indicate a horizontal acquisition of the receptor in these species, resulting in a change in the receptor partner of CarI within E. carotovora. In E. carotovora, the CarI/R system is implied in the production of carbapenem, an antibiotic. In the majority of LuxI/R systems in family B, the two genes corresponding to the inducer and the receptor are adjacent. However, carI (also named expI) and carR are not linked (von Bodman, Bauer, and Coplin 2003), supporting the hypothesis of the independent acquisition of carR. Moreover, a different gene, expR, is adjacent to carI, but no genes regulated by ExpR have been identified (Andersson et al. 2000). This could indicate that, after the acquisition of carR, some expR functions, particularly the activation of expI expression have been assumed by the new gene. If the carbapenem operon was acquired at the same time as carR, the selective advantage of being able to produce this antibiotic would explain the switch between carR and expR. It has been shown that overexpression of expR decreases the virulence of E. carotovora when the ExpR protein is attached to the inducer (Andersson et al. 2000). This suggests that expR is still functional but acts as a repressor of virulence by sequestering inducer molecules. In S. marcescens, CarR is also implicated in the production of carbapenem, and the gene is also located near the first gene carA of the operon (Thomson et al. 2000). There is a difference between the two mechanisms. In Serratia, the production of carbapenem is independent of the production of a diffusible signal (Cox et al. 1998). S. marcescens and E. carotovara are the only gram-negative bacteria known to be able to produce this antibiotic. The other bacteria known to possess this property are Streptomyces species, gram-positive bacteria.
Gene Duplications
The two trees are globally in agreement with the SSU rRNA phylogeny for relationships within major clades (fig. 2).
Yersinia pestis and Y. pseudotuberculosis are the only two species possessing genes from the two groups of paralogs (both are present in Serratia but not in the same genome). We performed a BlastP search against the uncompleted sequence for the genomes of E. chrysanthemi, E. carotovora, and Y. enterolitica to find homologous genes of YtbI/R and YspI/R. However, no genes other than those used in this study were detected. The sporadic distribution of the paralogous genes suggests that horizontal transfer occurred in an ancestor of Yersinia. However, ancient duplication followed by extensive loss of one or the other paralog could also explain the observed pattern. One scenario involving ancestral duplication is presented in figure 3B. Several other explanations are also consistent with the observations but require numerous events of duplication, transfer, and/or loss.
Evolution of LuxS
We have reconstructed the phylogenetic tree of the LuxS protein (fig. 4). The tree presented was obtained using the NJ method, with 500 bootstrap replicates and with the correction for the distribution of changes among sites, and the other methods yielded the identical topology. As in the SSU RNA tree (fig. 2), the Firmicutes forms a clade separate from the Proteobacteria. Inside the Proteobacteria, each division (
, b, and
) is distinct. Although the
-Proteobacteria are paraphyletic in this tree, this branching pattern is not well supported.
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We also find an actinobacterium, Bifidobacterium longum, as sister group to the Firmicutes Lactobacillus plantarum and Lactococcus lactis, and several Streptococcus. B. longum colonizes the human gastrointestinal tract and is considered as an important commensal (Schell et al. 2002). Interestingly, L. plantarum and L. lactis are known to be natural inhabitants of the human gastrointestinal tract (Bolotin et al. 2001; Kleerebezem et al. 2003). Thus, the proximity of the habitat of these species might explain the possibility of gene transfers among them.
The cohesion of the group of the -Proteobacteria indicates that the presence of luxS is ancestral in this group, possibly predating the interaction of these bacteria with metazoan hosts.
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Conclusions |
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Nonetheless, these results do indicate an important role of horizontal transfer in generating the current distribution of the QS genes across bacterial species. We document fewer instances of LGT than do Gray and Garey (2001), who considered the LuxI/R system as a single family rather than two. Combining the two families into a single analysis required the hypothesis of additional instances of LGT by these authors. More recently, Boucher et al. (2003) reanalyzed the data set of Gray and Garey (2001), adding some new sequences. They found the same LGT events, including ones that are based on the failure to separate the two families, plus some new cases of LGT. We confirm one of these additional cases, which concerns transfer from ß-Proteobacteria to P. aeruginosa. Boucher et al. (2003) also propose independent events of LGT for spnI, sprI, and smaI in Serratia species and show that remnants of insertion sequences flank those genes. In our phylogeny, those genes do not present aberrant positions, and LGT without phylogenetic disruption or intrachromosomal rearrangements could explain these cases.
Horizontal transfer is particularly clear for the luxS genes transferred to several lineages of bacteria from Firmicutes, the carR genes in E. carotovora and S. marcescens, and certain systems of family A, such as the RhlI/R system in P. aeruginosa. The case of carI/R in E. carotovora is an interesting example of the replacement of one receptor by another, while depending on the native inducer gene and retaining the functionality of the native receptor but reassigning its role to that of negative regulator. As in the cases of the LasI/R and RhlI/R systems in P. aeruginosa, this illustrates the possibility of integrating an acquired gene into a preexisting regulatory pathway. The gain of such systems is of particular interest in pathogenic species. It provides a mechanism for regulating virulence genes with respect to the density of members of their own species and, in some cases, of other species. These capabilities can affect competitive ability, as in the case of antibiotic production by E. carotovora and S. marcescens, and thus will typically be under strong selection. Strong positive selection for the newly acquired trait has been hypothesized to be important for horizontal gene transfer (e.g., Ochman, Lawrence, and Groisman 2000).
For the LuxI/R families, receptor genes appear occasionally to lose their inducer gene partners, or vice versa, with no replacement recognizable on the basis of sequence homology. The most striking case of this is the sdiA receptor genes in the enteric bacteria, which appear to function in receiving signals from other bacterial species (Smith and Ahmer 2003). The variety of commensal and competitive interactions among bacteria in natural communities is expected to create many situations in which reception or emission of a signal may be independently favored.
The presence of homologous signaling systems within some genomes appears to reflect both duplication and horizontal transfer, in different cases. This indicates that the regulatory genes in bacteria can adapt to new target genes either when they are horizontally transmitted or when they are duplicated. The QS systems are regarded as new targets for antimicrobial strategies. In this perspective, it is important to consider the potential implication of horizontal transfers in the reacquisition of virulence.
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Footnotes |
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