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Quorum Sensing☆
Quorum Sensing☆ SP Diggle and P Williams, University of Nottingham, Nottingham, United Kingdom r 2017 Elsevier Inc. All rights reserved.
Glossary Altruism A behavior that increases another individual’s fitness at a cost to one’s own. Autoinduction The induction of a regulatory cascade in quorum sensing. It is triggered in response to the concentration of quorum sensing signal molecule (or autoinducer) accumulating to a threshold concentration. Cheat An individual who does not cooperate (or cooperates less than their fair share), but can potentially gain the benefit from others cooperation. Cooperation A behavior that benefits another individual (the recipient) and which is maintained (at least partially) because of its beneficial effect on the recipient.
Cue Something that can be used by an individual as a guide for future action. Quorum The minimum number of bacterial cells in a population that must be present to induce a behavioral change within the population as a whole. Response regulator A regulatory protein consisting of two domains, a DNA-binding domain and an effector domain, which, in quorum sensing systems, frequently contains the site at which the signal molecule binds. Signal Something that alters the behavior of another individual, which evolved because of that effect, and which is effective because the receiver’s response has also evolved.
What Is Quorum Sensing? Although unicellular, bacteria are highly interactive and display a number of collective social behaviors, many of which are regulated by cell-to-cell communication (quorum sensing, QS). At its simplest, QS describes the phenomenon whereby the accumulation of self-generated diffusible “signaling” molecules in the surrounding environment enables a single bacterial cell to sense the number of other bacterial cells present, such that the population as a whole is able to make a coordinated response (Fig. 1). The signal produced frequently regulates its own production and this generates positive feedback (autoinduction) which rapidly increases QS signal synthesis. At a critical threshold signal molecule concentration, and hence cell population density (ie, when the population is “quorate”), the binding of the signal to a response regulator protein results in the switch on (or off) of genes controlled by QS, thereby coordinating the collective behavior of the population. The size of a “quorum” is not fixed but will be determined by the relative rates of production and loss via degradation or diffusion of the signaling molecule(s). While QS as a term has been in general use since 1994, cell-to-cell communication in bacteria has a history that dates back to the early 1960s from work on Myxococcus xanthus and Streptomyces griseus fruiting body formation and streptomycin production, respectively. The classical description of cell density-dependent behavior originates from an observation that the addition of cell-free culture supernatants from high-density cultures of the marine luminescent bacterium Vibrio fischeri to low-density cultures, induced bioluminescence due to the presence of an “autoinducer” substance. The autoinducer was later identified as an N-acylhomoserine lactone (AHL), specifically N-(3-oxohexanoyl) homoserine lactone (3O-C6-HSL). Subsequently, 3O-C6-HSL and related AHLs were discovered in bacteria other than luminescent marine vibrios including the human and plant pathogens Pseudomonas aeruginosa and Erwinia carotovora. Bacteria are now known to employ a diverse range of chemically distinct QS signal molecules which, in conjunction with their cognate signal synthase(s) and the associated response regulator protein(s), form an interdependent regulatory network that governs how a bacterial population will respond collectively to localized environmental challenges (Fig. 2). QS systems control a variety of different social behaviors that vary from species to species. In addition to bioluminescence, these include swimming and swarming motility, symbiosis, protein secretion, plasmid exchange, secondary metabolite production, and biofilm development; for many pathogenic bacteria, QS is required for virulence in animals, plants, and insects.
What Constitutes a QS Signal? Bacteria release a large number of metabolic products into their immediate growth environment. Consequently, for a molecule to be classed as a QS signal, it should display a number of important characteristics: (1) the production of a QS signal should take place during specific stages of growth or in response to particular environmental challenges; (2) a QS signal should accumulate in the extracellular environment and be recognized by a specific bacterial receptor; (3) the accumulation of a critical threshold ☆
Change History: November 2015. P. Williams and S.P. Diggle added a new Fig. 1.
Reference Module in Life Sciences
doi:10.1016/B978-0-12-809633-8.06991-0
1
2
Quorum Sensing
Fig. 1 QS – bacterial cell-to-cell communication. At low bacterial cell population densities, the concentration of QS signal molecules is insufficient to activate or repress QS-controlled traits. At high cell population densities, a high concentration of signal in the environment results in a coordinated collective response by the bacterial population. The production of many QS-controlled traits (eg, exoenzymes) are more efficient and beneficial to individual bacteria at high population densities.
concentration of the QS signal should generate a concerted physiological response, and (4) the cellular response should extend beyond the physiological changes required to metabolize or detoxify the putative signal molecule. However, some caution should be exercised when applying the term “signal” to a molecule. For a molecule to be classed as a true signal, it should benefit the receiver cell to respond and in turn, the response should benefit the producer cell. Alternatively, a molecule may be used as a cue by a receiver, which may guide a future action. In this case, the molecule may not benefit the producer and therefore cannot be strictly defined as a signal. A third possibility is that a molecule may “coerce” a receiver cell into an action, which may be detrimental to its fitness, yet this action benefits the producer cell. Again, this cannot be classed as true signaling. Such interactions become especially important when an interaction is between two different bacterial species or between bacteria and higher organisms.
QS and Communication Between Bacterial Species and Higher Organisms Although most laboratory investigations of QS initially focused on elucidating the chemical identity of the QS signal molecule and the associated signal transduction and target structural genes in a single species, most bacteria in natural environments are found in multispecies communities. Since different bacterial species may make the same, chemically related or chemically distinct QS signal molecules, this has given rise to the concept of bacterial “cross-talk” in which one species responds to a QS molecule made by a different species such that they may share information. In this context, for example, bacteria such as Escherichia coli and Salmonella which do not produce AHLs nevertheless possess an AHL response regulator protein which enables them to respond to AHLs made by other bacteria present in the local environment. This implies that one bacterial species may be capable of “eavesdropping” on another species although such unicellular communication may alternatively result in the coercion of the responsive species into making a costly response for the benefit of the signal producer. Thus, within multispecies bacterial communities, sophisticated multisignal QS networks promoting cooperation and conflict between species are likely to exist. The membership of QS activities within such communities are likely to be further modulated by the expression of QS signal degrading enzymes such as the lactonases and acylases which can inactive AHL signals. QS signal molecules may also impact on the behavior of higher organisms. For example, zoospores of the green macroalga, Ulva sense AHLs, and preferentially select surfaces for colonization which harbor AHL-producing bacterial biofilm communities, although the biological advantages for either algae or bacteria are not yet clear. AHLs produced by beneficial tomato rootassociated bacteria stimulate salicylic acid production in tomato plant leaves which in turn enhances systemic resistance toward fungal pathogens. In addition to controlling virulence factor production, bacterial QS signal molecules may also influence both the immune and cardiovascular systems of mammals so enhancing ability of the infecting pathogen to cause disease.
Quorum Sensing
3
Fig. 2 Some examples of QS signal molecules: (a)–(c) N-acylhomoserine lactone (AHL) family where R ranges from C1 to C15; this class of QS signals is produced by over 100 different Gram-negative bacterial species, (d) AHL made by environmental bacteria such as Rhodopseudomonas palustris, (e) DSF produced by Xanthomonas campestris, (f) PQS, produced by Pseudomonas aeruginosa, (g) AI-2 borate complex employed by Vibrio fischeri; AI-2 type signals are produced by both Gram-positive and Gram-negative bacteria, (h) group 1 autoinducing peptide (AIP) made by Staphylococcus aureus.
Evolutionary Implications of QS QS is often described as a behavior performed by individual bacterial cells for the overall good of the population. Accounting for such altruism is problematic for evolutionary biologists because such cooperative actions are costly for individuals to perform, yet increase the fitness of others. Such behaviors should be exploitable by non-cooperating cheats, and QS has been shown to be exploitable by nonresponding cheats, which arise in both laboratory cultures and in experimental animal infection models. Such mutants have also been found together with their QS-competent parent strains in clinical samples from patients with chronic bacterial infections and consequently explanations are being sought as to why QS is maintained in natural populations. While bacterial QS signal molecules have been detected in both environmental and clinical samples, and the mechanism by which such molecules modulate gene expression is not in doubt, QS as defined here has been suggested to be an artifact of laboratory growth conditions. Instead, an alternative view in which individual cells probe their surroundings by assessing the rate of diffusion which QS signal molecules move away from producer cells has been proposed. Such “diffusion sensing” (DS) could allow cells to regulate the secretion of costly extracellular enzymes to minimize losses as a consequence of extra-cellular diffusion and mixing. In an evolutionary context, while QS provides group benefits, DS is more beneficial to the individual. Furthermore,
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Quorum Sensing
the production of diffusible signal molecules may have initially evolved for one reason (eg, DS), but is now maintained for another (eg, QS). The two hypotheses need not be in conflict as it may be the case that DS benefits are crucial for the maintenance of this trait, yet are still monitored for QS purposes. Both functions are likely to be of importance in understanding when and why these signal molecules are produced and how QS systems evolve and are maintained in natural bacterial communities.
Further Reading Amara, N., Krom, B.P., Kaufmann, G.F., Meijler, M.M., 2011. Macromolecular inhibition of quorum sensing: Enzymes, antibodies, and beyond. Chemical Reviews 111 (1), 195–208. doi:10.1021/cr100101c. Blackwell, H.E., Fuqua, C., 2011. Introduction to bacterial signals and chemical communication. Chemical Reviews 111 (1), 1–3. doi:10.1021/cr100407j. Churchill, M.E.A., Chen, L., 2011. Structural basis of acyl-homoserine lactone-dependent signaling. Chemical Reviews 111 (1), 68–85. doi:10.1021/cr1000817. Decho, A.W., Frey, R.L., Ferry, J.L., 2011. Chemical challenges to bacterial AHL signaling in the environment. Chemical Reviews 111 (1), 86–99. doi:10.1021/cr100311q. Dembitsky, V.M., Al Quntar, A.A.A., Srebnik, M., 2011. Natural and synthetic small boron-containing molecules as potential inhibitors of bacterial and fungal quorum sensing. Chemical Reviews 111 (1), 209–237. doi:10.1021/cr100093b. Deng, Y., Wu, J., Tao, F., Zhang, L.-H., 2011. Listening to a new language: DSF-based quorum sensing in gram-negative bacteria. Chemical Reviews 111 (1), 160–179. doi:10.1021/cr100354f. Galloway, W.R.J.D., Hodgkinson, J.T., Bowden, S.D., Welch, M., Spring, D.R., 2011. Quorum sensing in Gram-negative bacteria: Small-molecule modulation of AHL and AI-2 quorum sensing pathways. Chemical Reviews 111 (1), 28–67. doi:10.1021/cr100109t. Gibbs, K.A., Greenberg, E.P., 2011. Territoriality in Proteus: Advertisement and aggression. Chemical Reviews 111 (1), 188–194. doi:10.1021/cr100051v. Goryachev, A.B., 2011. Understanding bacterial cell–cell communication with computational modeling. Chemical Reviews 111 (1), 238–250. doi:10.1021/cr100286z. Huse, H., Whiteley, M., 2011. 4-Quinolones: Smart phones of the microbial world. Chemical Reviews 111 (1), 152–159. doi:10.1021/cr100063u. Joint, I., Downie, J.A., Williams, P. (Eds.), 2007. Bacterial conversations: Talking, listening and eavesdropping. Philosophical Transactions of the Royal Society B 362, 1113–1249. Stevens, A.M., Queneau, Y., Soulère, L., Bodman, S.V., Doutheau, A., 2011. Mechanisms and synthetic modulators of AHL-dependent gene regulation. Chemical Reviews 111 (1), 4–27. doi:10.1021/cr100064s. Teplitski, M., Mathesius, U., Rumbaugh, K.P., 2011. Perception and degradation of N-acyl homoserine lactone quorum sensing signals by mammalian and plant cells. Chemical Reviews 111 (1), 100–116. doi:10.1021/cr100045m. Thoendel, M., Kavanaugh, J.S., Flack, C.E., Horswill, A.R., 2011. Peptide signaling in the staphylococci. Chemical Reviews 111 (1), 117–151. doi:10.1021/cr100370n. Willey, J.M., Gaskell, A.A., 2011. Morphogenetic signaling molecules of the streptomycetes. Chemical Reviews 111 (1), 174–187. doi:10.1021/cr1000404.
Relevant Website http://www.nottingham.ac.uk/quorum The Quorum Sensing Site.
Glossary Altruism A behavior that increases another individual’s fitness at a cost to one’s own. Autoinduction The induction of a regulatory cascade in quorum sensing. It is triggered in response to the concentration of quorum sensing signal molecule (or autoinducer) accumulating to a threshold concentration. Cheat An individual who does not cooperate (or cooperates less than their fair share), but can potentially gain the benefit from others cooperation. Cooperation A behavior that benefits another individual (the recipient) and which is maintained (at least partially) because of its beneficial effect on the recipient.
Cue Something that can be used by an individual as a guide for future action. Quorum The minimum number of bacterial cells in a population that must be present to induce a behavioral change within the population as a whole. Response regulator A regulatory protein consisting of two domains, a DNA-binding domain and an effector domain, which, in quorum sensing systems, frequently contains the site at which the signal molecule binds. Signal Something that alters the behavior of another individual, which evolved because of that effect, and which is effective because the receiver’s response has also evolved.
What Is Quorum Sensing? Although unicellular, bacteria are highly interactive and display a number of collective social behaviors, many of which are regulated by cell-to-cell communication (quorum sensing, QS). At its simplest, QS describes the phenomenon whereby the accumulation of self-generated diffusible “signaling” molecules in the surrounding environment enables a single bacterial cell to sense the number of other bacterial cells present, such that the population as a whole is able to make a coordinated response (Fig. 1). The signal produced frequently regulates its own production and this generates positive feedback (autoinduction) which rapidly increases QS signal synthesis. At a critical threshold signal molecule concentration, and hence cell population density (ie, when the population is “quorate”), the binding of the signal to a response regulator protein results in the switch on (or off) of genes controlled by QS, thereby coordinating the collective behavior of the population. The size of a “quorum” is not fixed but will be determined by the relative rates of production and loss via degradation or diffusion of the signaling molecule(s). While QS as a term has been in general use since 1994, cell-to-cell communication in bacteria has a history that dates back to the early 1960s from work on Myxococcus xanthus and Streptomyces griseus fruiting body formation and streptomycin production, respectively. The classical description of cell density-dependent behavior originates from an observation that the addition of cell-free culture supernatants from high-density cultures of the marine luminescent bacterium Vibrio fischeri to low-density cultures, induced bioluminescence due to the presence of an “autoinducer” substance. The autoinducer was later identified as an N-acylhomoserine lactone (AHL), specifically N-(3-oxohexanoyl) homoserine lactone (3O-C6-HSL). Subsequently, 3O-C6-HSL and related AHLs were discovered in bacteria other than luminescent marine vibrios including the human and plant pathogens Pseudomonas aeruginosa and Erwinia carotovora. Bacteria are now known to employ a diverse range of chemically distinct QS signal molecules which, in conjunction with their cognate signal synthase(s) and the associated response regulator protein(s), form an interdependent regulatory network that governs how a bacterial population will respond collectively to localized environmental challenges (Fig. 2). QS systems control a variety of different social behaviors that vary from species to species. In addition to bioluminescence, these include swimming and swarming motility, symbiosis, protein secretion, plasmid exchange, secondary metabolite production, and biofilm development; for many pathogenic bacteria, QS is required for virulence in animals, plants, and insects.
What Constitutes a QS Signal? Bacteria release a large number of metabolic products into their immediate growth environment. Consequently, for a molecule to be classed as a QS signal, it should display a number of important characteristics: (1) the production of a QS signal should take place during specific stages of growth or in response to particular environmental challenges; (2) a QS signal should accumulate in the extracellular environment and be recognized by a specific bacterial receptor; (3) the accumulation of a critical threshold ☆
Change History: November 2015. P. Williams and S.P. Diggle added a new Fig. 1.
Reference Module in Life Sciences
doi:10.1016/B978-0-12-809633-8.06991-0
1
2
Quorum Sensing
Fig. 1 QS – bacterial cell-to-cell communication. At low bacterial cell population densities, the concentration of QS signal molecules is insufficient to activate or repress QS-controlled traits. At high cell population densities, a high concentration of signal in the environment results in a coordinated collective response by the bacterial population. The production of many QS-controlled traits (eg, exoenzymes) are more efficient and beneficial to individual bacteria at high population densities.
concentration of the QS signal should generate a concerted physiological response, and (4) the cellular response should extend beyond the physiological changes required to metabolize or detoxify the putative signal molecule. However, some caution should be exercised when applying the term “signal” to a molecule. For a molecule to be classed as a true signal, it should benefit the receiver cell to respond and in turn, the response should benefit the producer cell. Alternatively, a molecule may be used as a cue by a receiver, which may guide a future action. In this case, the molecule may not benefit the producer and therefore cannot be strictly defined as a signal. A third possibility is that a molecule may “coerce” a receiver cell into an action, which may be detrimental to its fitness, yet this action benefits the producer cell. Again, this cannot be classed as true signaling. Such interactions become especially important when an interaction is between two different bacterial species or between bacteria and higher organisms.
QS and Communication Between Bacterial Species and Higher Organisms Although most laboratory investigations of QS initially focused on elucidating the chemical identity of the QS signal molecule and the associated signal transduction and target structural genes in a single species, most bacteria in natural environments are found in multispecies communities. Since different bacterial species may make the same, chemically related or chemically distinct QS signal molecules, this has given rise to the concept of bacterial “cross-talk” in which one species responds to a QS molecule made by a different species such that they may share information. In this context, for example, bacteria such as Escherichia coli and Salmonella which do not produce AHLs nevertheless possess an AHL response regulator protein which enables them to respond to AHLs made by other bacteria present in the local environment. This implies that one bacterial species may be capable of “eavesdropping” on another species although such unicellular communication may alternatively result in the coercion of the responsive species into making a costly response for the benefit of the signal producer. Thus, within multispecies bacterial communities, sophisticated multisignal QS networks promoting cooperation and conflict between species are likely to exist. The membership of QS activities within such communities are likely to be further modulated by the expression of QS signal degrading enzymes such as the lactonases and acylases which can inactive AHL signals. QS signal molecules may also impact on the behavior of higher organisms. For example, zoospores of the green macroalga, Ulva sense AHLs, and preferentially select surfaces for colonization which harbor AHL-producing bacterial biofilm communities, although the biological advantages for either algae or bacteria are not yet clear. AHLs produced by beneficial tomato rootassociated bacteria stimulate salicylic acid production in tomato plant leaves which in turn enhances systemic resistance toward fungal pathogens. In addition to controlling virulence factor production, bacterial QS signal molecules may also influence both the immune and cardiovascular systems of mammals so enhancing ability of the infecting pathogen to cause disease.
Quorum Sensing
3
Fig. 2 Some examples of QS signal molecules: (a)–(c) N-acylhomoserine lactone (AHL) family where R ranges from C1 to C15; this class of QS signals is produced by over 100 different Gram-negative bacterial species, (d) AHL made by environmental bacteria such as Rhodopseudomonas palustris, (e) DSF produced by Xanthomonas campestris, (f) PQS, produced by Pseudomonas aeruginosa, (g) AI-2 borate complex employed by Vibrio fischeri; AI-2 type signals are produced by both Gram-positive and Gram-negative bacteria, (h) group 1 autoinducing peptide (AIP) made by Staphylococcus aureus.
Evolutionary Implications of QS QS is often described as a behavior performed by individual bacterial cells for the overall good of the population. Accounting for such altruism is problematic for evolutionary biologists because such cooperative actions are costly for individuals to perform, yet increase the fitness of others. Such behaviors should be exploitable by non-cooperating cheats, and QS has been shown to be exploitable by nonresponding cheats, which arise in both laboratory cultures and in experimental animal infection models. Such mutants have also been found together with their QS-competent parent strains in clinical samples from patients with chronic bacterial infections and consequently explanations are being sought as to why QS is maintained in natural populations. While bacterial QS signal molecules have been detected in both environmental and clinical samples, and the mechanism by which such molecules modulate gene expression is not in doubt, QS as defined here has been suggested to be an artifact of laboratory growth conditions. Instead, an alternative view in which individual cells probe their surroundings by assessing the rate of diffusion which QS signal molecules move away from producer cells has been proposed. Such “diffusion sensing” (DS) could allow cells to regulate the secretion of costly extracellular enzymes to minimize losses as a consequence of extra-cellular diffusion and mixing. In an evolutionary context, while QS provides group benefits, DS is more beneficial to the individual. Furthermore,
4
Quorum Sensing
the production of diffusible signal molecules may have initially evolved for one reason (eg, DS), but is now maintained for another (eg, QS). The two hypotheses need not be in conflict as it may be the case that DS benefits are crucial for the maintenance of this trait, yet are still monitored for QS purposes. Both functions are likely to be of importance in understanding when and why these signal molecules are produced and how QS systems evolve and are maintained in natural bacterial communities.
Further Reading Amara, N., Krom, B.P., Kaufmann, G.F., Meijler, M.M., 2011. Macromolecular inhibition of quorum sensing: Enzymes, antibodies, and beyond. Chemical Reviews 111 (1), 195–208. doi:10.1021/cr100101c. Blackwell, H.E., Fuqua, C., 2011. Introduction to bacterial signals and chemical communication. Chemical Reviews 111 (1), 1–3. doi:10.1021/cr100407j. Churchill, M.E.A., Chen, L., 2011. Structural basis of acyl-homoserine lactone-dependent signaling. Chemical Reviews 111 (1), 68–85. doi:10.1021/cr1000817. Decho, A.W., Frey, R.L., Ferry, J.L., 2011. Chemical challenges to bacterial AHL signaling in the environment. Chemical Reviews 111 (1), 86–99. doi:10.1021/cr100311q. Dembitsky, V.M., Al Quntar, A.A.A., Srebnik, M., 2011. Natural and synthetic small boron-containing molecules as potential inhibitors of bacterial and fungal quorum sensing. Chemical Reviews 111 (1), 209–237. doi:10.1021/cr100093b. Deng, Y., Wu, J., Tao, F., Zhang, L.-H., 2011. Listening to a new language: DSF-based quorum sensing in gram-negative bacteria. Chemical Reviews 111 (1), 160–179. doi:10.1021/cr100354f. Galloway, W.R.J.D., Hodgkinson, J.T., Bowden, S.D., Welch, M., Spring, D.R., 2011. Quorum sensing in Gram-negative bacteria: Small-molecule modulation of AHL and AI-2 quorum sensing pathways. Chemical Reviews 111 (1), 28–67. doi:10.1021/cr100109t. Gibbs, K.A., Greenberg, E.P., 2011. Territoriality in Proteus: Advertisement and aggression. Chemical Reviews 111 (1), 188–194. doi:10.1021/cr100051v. Goryachev, A.B., 2011. Understanding bacterial cell–cell communication with computational modeling. Chemical Reviews 111 (1), 238–250. doi:10.1021/cr100286z. Huse, H., Whiteley, M., 2011. 4-Quinolones: Smart phones of the microbial world. Chemical Reviews 111 (1), 152–159. doi:10.1021/cr100063u. Joint, I., Downie, J.A., Williams, P. (Eds.), 2007. Bacterial conversations: Talking, listening and eavesdropping. Philosophical Transactions of the Royal Society B 362, 1113–1249. Stevens, A.M., Queneau, Y., Soulère, L., Bodman, S.V., Doutheau, A., 2011. Mechanisms and synthetic modulators of AHL-dependent gene regulation. Chemical Reviews 111 (1), 4–27. doi:10.1021/cr100064s. Teplitski, M., Mathesius, U., Rumbaugh, K.P., 2011. Perception and degradation of N-acyl homoserine lactone quorum sensing signals by mammalian and plant cells. Chemical Reviews 111 (1), 100–116. doi:10.1021/cr100045m. Thoendel, M., Kavanaugh, J.S., Flack, C.E., Horswill, A.R., 2011. Peptide signaling in the staphylococci. Chemical Reviews 111 (1), 117–151. doi:10.1021/cr100370n. Willey, J.M., Gaskell, A.A., 2011. Morphogenetic signaling molecules of the streptomycetes. Chemical Reviews 111 (1), 174–187. doi:10.1021/cr1000404.
Relevant Website http://www.nottingham.ac.uk/quorum The Quorum Sensing Site.