Bibliography (BibTeX).bib

@Article{Allen2016,
author = {Allen, RC and McNally, L and Popat, R and Brown, SP}, 
title = {Quorum sensing protects bacterial co-operation from exploitation by cheats.}, 
journal = {ISME J}, 
volume = {10}, 
number = {7}, 
pages = {1706--1716}, 
year = {2016}, 
abstract = {Quorum sensing (QS) is a cell-cell communication system found in many bacterial species, commonly controlling secreted co-operative traits, including extracellular digestive enzymes. We show that the canonical QS regulatory architecture allows bacteria to sense the genotypic composition of high-density populations, and limit co-operative investments to social environments enriched for co-operators. Using high-density populations of the opportunistic pathogen Pseudomonas aeruginosa we map per-capita signal and co-operative enzyme investment in the wild type as a function of the frequency of non-responder cheats. We demonstrate mathematically and experimentally that the observed response rule of `co-operate when surrounded by co-operators' allows bacteria to match their investment in co-operation to the composition of the group, therefore allowing the maintenance of co-operation at lower levels of population structuring (that is, lower relatedness). Similar behavioural responses have been described in vertebrates under the banner of `generalised reciprocity'. Our results suggest that mechanisms of reciprocity are not confined to taxa with advanced cognition, and can be implemented at the cellular level via positive feedback circuits.}, 
location = {Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.}, }

@Article{Boedicker2009,
author = {Boedicker, JQ and Vincent, ME and Ismagilov, RF}, 
title = {Microfluidic confinement of single cells of bacteria in small volumes initiates high-density behavior of quorum sensing and growth and reveals its variability.}, 
journal = {Angew Chem Int Ed Engl}, 
volume = {48}, 
number = {32}, 
pages = {5908--5911}, 
year = {2009}, 
location = {Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.}, }

@Book{Bolouri2008,
author = {Bolouri, Hamid}, 
title = {Computational Modeling of Gene Regulatory Networks: A Primer}, 
pages = {341}, 
publisher = {Imperial College Press}, 
year = {2008}, 
abstract = {This book serves as an introduction to the myriad computational approaches to gene regulatory modeling and analysis, and is written specifically with experimental biologists in mind. Mathematical jargon is avoided and explanations are given in intuitive terms. In cases where equations are unavoidable, they are derived from first principles or, at the very least, an intuitive description is provided. Extensive examples and a large number of model descriptions are provided for use in both classroom exercises as well as self-guided exploration and learning. As such, the book is ideal for self-learning and also as the basis of a semester-long course for undergraduate and graduate students in molecular biology, bioengineering, genome sciences, or systems biology.}, }

@Article{Bottomley2007,
author = {Bottomley, MJ and Muraglia, E and Bazzo, R and Carfì, A}, 
title = {Molecular insights into quorum sensing in the human pathogen {\emph{Pseudomonas aeruginosa}} from the structure of the virulence regulator LasR bound to its autoinducer.}, 
journal = {J Biol Chem}, 
volume = {282}, 
number = {18}, 
pages = {13592--13600}, 
year = {2007}, 
abstract = {Many Gram-negative bacteria communicate via molecules called autoinducers to coordinate the activities of their populations. Such communication is termed quorum sensing and can regulate pathogenic virulence factor production and antimicrobial resistance. The quorum sensing system of Pseudomonas aeruginosa is currently the most intensively researched, because this bacterium is an opportunistic human pathogen annually responsible for the death of thousands of cystic fibrosis sufferers and many other immunocompromised individuals. Quorum sensing inhibitors can attenuate the pathogenicity of P. aeruginosa. Here we present the crystal structure of the P. aeruginosa LasR ligand-binding domain bound to its autoinducer 3-oxo-C(12)-acylhomoserine lactone. The structure is a symmetrical dimer, with each monomer exhibiting an alpha-beta-alpha fold similar to the TraR and SdiA quorum sensing proteins of Agrobacterium tumefaciens and Escherichia coli. The structure was determined up to 1.8-A resolution and reveals the atomic interactions between LasR and its autoinducer. The monomer structures of LasR, TraR, and SdiA are comparable but display differences in their quaternary organization. Inspection of their binding sites shows some unexpected variations resulting in quite different conformations of their bound autoinducers. We modeled interactions between LasR and various quorum sensing inhibitors, yielding insight into their possible mechanisms of action. The structure also provides a platform for the optimization, or de novo design, of quorum sensing inhibitors.}, 
location = {Istituto di Ricerche di Biologia Molecolare, Via Pontina Km 30.600, 00040 Pomezia, Rome, Italy. matthew_bottomley@merck.com}, 
keywords = {lasR},}

@Article{Brachmann2013,
author = {Brachmann, AO and Brameyer, S and Kresovic, D and Hitkova, I and Kopp, Y and Manske, C and Schubert, K and Bode, HB and Heermann, R}, 
title = {Pyrones as bacterial signaling molecules.}, 
journal = {Nat Chem Biol}, 
volume = {9}, 
number = {9}, 
pages = {573--578}, 
year = {2013}, 
abstract = {Bacteria communicate via small diffusible molecules and thereby mediate group-coordinated behavior, a process referred to as quorum sensing. The prototypical quorum sensing system found in Gram-negative bacteria consists of a LuxI-type autoinducer synthase that produces N-acyl homoserine lactones (AHLs) as signals and a LuxR-type receptor that detects the AHLs to control expression of specific genes. However, many proteobacteria have proteins with homology to LuxR receptors yet lack any cognate LuxI-like AHL synthase. Here we show that in the insect pathogen Photorhabdus luminescens the orphan LuxR-type receptor PluR detects endogenously produced α-pyrones that serve as signaling molecules at low nanomolar concentrations. Additionally, the ketosynthase PpyS was identified as pyrone synthase. Reconstitution of the entire system containing PluR, the PluR-target operon we termed pcf and PpyS in Escherichia coli demonstrated that the cell-cell communication circuit is portable. Our research thus deorphanizes a signaling system and suggests that additional modes of bacterial communication may await discovery.}, 
location = {1] Merck Stiftungsprofessur für Molekulare Biotechnologie, Goethe-Universität Frankfurt, Frankfurt, Germany. [2].}, }

@Article{Brown2013,
author = {Brown, D}, 
title = {Linking molecular and population processes in mathematical models of quorum sensing.}, 
journal = {Bull Math Biol}, 
volume = {75}, 
number = {10}, 
pages = {1813--1839}, 
year = {2013}, 
abstract = {Many bacteria alter their behaviors as a function of population density, via a process known as quorum sensing (QS). QS is achieved by the synthesis and detection of diffusible signal molecules, often involving complex signal transduction pathways and regulatory networks. Mathematical models have been developed to investigate a number of aspects of QS, resulting in a wide range of model structures; many have focused on either the molecular or the population scale. In this paper, I show that many published models fail to satisfy physical constraints (such as conservation of matter) or rely on a priori assumptions that may not be valid. I present new, simple models of canonical Gram-negative and Gram-positive QS systems, in both well-mixed and biofilm populations, focusing on the interaction between molecular and population processes. I show that this interaction may be crucial for several important features of QS, including bistability and the localization of QS in space. The results highlight the need to link molecular and population processes carefully in QS models, provide a general framework for understanding the behavior of complex system-specific models, and suggest new directions for both theoretical and experimental work.}, 
location = {Colorado College, Colorado Sprigs, CO, USA, dbrown@coloradocollege.edu.}, }

@Article{Buchler2003,
author = {Buchler, NE and Gerland, U and Hwa, T}, 
title = {On schemes of combinatorial transcription logic.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {100}, 
number = {9}, 
pages = {5136--5141}, 
year = {2003}, 
abstract = {Cells receive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate specific genetic responses. Here we explore theoretically the potentials and limitations of combinatorial signal integration at the level of cis-regulatory transcription control. Our analysis suggests that many complex transcription-control functions of the type encountered in higher eukaryotes are already implementable within the much simpler bacterial transcription system. Using a quantitative model of bacterial transcription and invoking only specific protein-DNA interaction and weak glue-like interaction between regulatory proteins, we show explicit schemes to implement regulatory logic functions of increasing complexity by appropriately selecting the strengths and arranging the relative positions of the relevant protein-binding DNA sequences in the cis-regulatory region. The architectures that emerge are naturally modular and evolvable. Our results suggest that the transcription regulatory apparatus is a  computing machine, belonging formally to the class of Boltzmann machines. Crucial to our results is the ability to regulate gene expression at a distance. In bacteria, this can be achieved for isolated genes via DNA looping controlled by the dimerization of DNA-bound proteins. However, if adopted extensively in the genome, long-distance interaction can cause unintentional intergenic cross talk, a detrimental side effect difficult to overcome by the known bacterial transcription-regulation systems. This may be a key factor limiting the genome-wide adoption of complex transcription control in bacteria. Implications of our findings for combinatorial transcription control in eukaryotes are discussed.}, 
location = {Department of Physics and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093-0319, USA.}, 
keywords = {logic},}

@Article{Casilag2016,
author = {Casilag, F and Lorenz, A and Krueger, J and Klawonn, F and Weiss, S and Häussler, S}, 
title = {The LasB Elastase of {\emph{Pseudomonas aeruginosa}} Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition.}, 
journal = {Infect Immun}, 
volume = {84}, 
number = {1}, 
pages = {162--171}, 
year = {2016}, 
abstract = {The opportunistic pathogen Pseudomonas aeruginosa is capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library of P. aeruginosa PA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism for P. aeruginosa to ensure the maintenance of protease-dependent immune-modulating functions.}, 
location = {Institute for Molecular Bacteriology, Twincore-Centre for Experimental and Clinical Infection Research, a joint venture of the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. Institute for Molecular Bacteriology, Twincore-Centre for Experimental and Clinical Infection Research, a joint venture of the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany. Institute for Molecular Bacteriology, Twincore-Centre for Experimental and Clinical Infection Research, a joint venture of the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. Department of Biostatistics, Helmholtz Centre for Infection Research, Braunschweig, Germany Department of Computer Science, Ostfalia University of Applied Sciences, Wolfenbüttel, Germany. Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany. Institute for Molecular Bacteriology, Twincore-Centre for Experimental and Clinical Infection Research, a joint venture of the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany Susanne.haeussler@helmholtz-hzi.de.}, 
keywords = {lasB, virulence},}

@Article{Chadha2022,
author = {Chadha, J and Harjai, K and Chhibber, S}, 
title = {Revisiting the virulence hallmarks of  {\emph{Pseudomonas aeruginosa:}} a chronicle through the perspective of quorum sensing.}, 
journal = {Environ Microbiol}, 
volume = {24}, 
number = {6}, 
pages = {2630--2656}, 
year = {2022}, 
abstract = {Pseudomonas aeruginosa is an opportunistic pathogen and the leading cause of mortality among immunocompromised patients in clinical setups. The hallmarks of virulence in P. aeruginosa encompass six biologically competent attributes that cumulatively drive disease progression in a multistep manner. These multifaceted hallmarks lay the principal foundation for rationalizing the complexities of pseudomonal infections. They include factors for host colonization and bacterial motility, biofilm formation, production of destructive enzymes, toxic secondary metabolites, iron-chelating siderophores and toxins. This arsenal of virulence hallmarks is fostered and stringently regulated by the bacterial signalling system called quorum sensing (QS). The central regulatory functions of QS in controlling the timely expression of these virulence hallmarks for adaptation and survival drive the disease outcome. This review describes the intricate mechanisms of QS in P. aeruginosa and its role in shaping bacterial responses, boosting bacterial fitness. We summarize the virulence hallmarks of P. aeruginosa, relating them with the QS circuitry in clinical infections. We also examine the role of QS in the development of drug resistance and propose a novel antivirulence therapy to combat P. aeruginosa infections. This can prove to be a next-generation therapy that may eventually become refractory to the use of conventional antimicrobial treatments.}, 
location = {Department of Microbiology, Panjab University, Chandigarh, India.}, }

@Article{Chugani2001,
author = {Chugani, SA and Whiteley, M and Lee, KM and D'Argenio, D and Manoil, C and Greenberg, EP}, 
title = {QscR, a modulator of quorum-sensing signal synthesis and virulence in  {\emph{Pseudomonas aeruginosa}}.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {98}, 
number = {5}, 
pages = {2752--2757}, 
year = {2001}, 
abstract = {The opportunistic pathogenic bacterium Pseudomonas aeruginosa uses quorum-sensing signaling systems as global regulators of virulence genes. There are two quorum-sensing signal receptor and signal generator pairs, LasR-LasI and RhlR-RhlI. The recently completed P. aeruginosa genome-sequencing project revealed a gene coding for a homolog of the signal receptors, LasR and RhlR. Here we describe a role for this gene, which we call qscR. The qscR gene product governs the timing of quorum-sensing-controlled gene expression and it dampens virulence in an insect model. We present evidence that suggests the primary role of QscR is repression of lasI. A qscR mutant produces the LasI-generated signal prematurely, and this results in premature transcription of a number of quorum-sensing-regulated genes. When fed to Drosophila melanogaster, the qscR mutant kills the animals more rapidly than the parental P. aeruginosa. The repression of lasI by QscR could serve to ensure that quorum-sensing-controlled genes are not activated in environments where they are not useful.}, 
location = {Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.}, }

@Article{Cigana2021,
author = {Cigana, Cristina and Castandet, Jérôme and Sprynski, Nicolas and Melessike, Medede and Beyria, Lilha and Ranucci, Serena and Alcalá-Franco, Beatriz and Rossi, Alice and Bragonzi, Alessandra and Zalacain, Magdalena}, 
title = {{\emph{Pseudomonas aeruginosa}} elastase contributes to the establishment of chronic lung colonization and modulates the immune response in a murine model}, 
journal = {Frontiers in Microbiology}, 
volume = {11}, 
pages = {620819}, 
year = {2021}, 
abstract = {Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular …}, 
keywords = {lasB, virulence},}

@Article{Cornforth2014,
author = {Cornforth, DM and Popat, R and McNally, L and Gurney, J and Scott-Phillips, TC and Ivens, A and Diggle, SP and Brown, SP}, 
title = {Combinatorial quorum sensing allows bacteria to resolve their social and physical environment.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {111}, 
number = {11}, 
pages = {4280--4284}, 
year = {2014}, 
abstract = {Quorum sensing (QS) is a cell-cell communication system that controls gene expression in many bacterial species, mediated by diffusible signal molecules. Although the intracellular regulatory mechanisms of QS are often well-understood, the functional roles of QS remain controversial. In particular, the use of multiple signals by many bacterial species poses a serious challenge to current functional theories. Here, we address this challenge by showing that bacteria can use multiple QS signals to infer both their social (density) and physical (mass-transfer) environment. Analytical and evolutionary simulation models show that the detection of, and response to, complex social/physical contrasts requires multiple signals with distinct half-lives and combinatorial (nonadditive) responses to signal concentrations. We test these predictions using the opportunistic pathogen Pseudomonas aeruginosa and demonstrate significant differences in signal decay between its two primary signal molecules, as well as diverse combinatorial responses to dual-signal inputs. QS is associated with the control of secreted factors, and we show that secretome genes are preferentially controlled by synergistic  responses to multiple signal inputs, ensuring the effective expression of secreted factors in high-density and low mass-transfer environments. Our results support a new functional hypothesis for the use of multiple signals and, more generally, show that bacteria are capable of combinatorial communication.}, 
location = {Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.}, 
keywords = {logic, lasB},}

@Article{deKievit2002,
author = {de Kievit, TR and Kakai, Y and Register, JK and Pesci, EC and Iglewski, BH}, 
title = {Role of the {\emph{Pseudomonas aeruginosa}} {\emph{las}} and {\emph{rhl}} quorum-sensing systems in {\emph{rhlI}} regulation.}, 
journal = {FEMS Microbiol Lett}, 
volume = {212}, 
number = {1}, 
pages = {101--106}, 
year = {2002}, 
abstract = {In Pseudomonas aeruginosa the LasR-LasI and RhlR-RhlI quorum-sensing (QS) systems control expression of numerous virulence genes in a population density-dependent fashion. In this study, we investigated regulation of the autoinducer synthase gene rhlI, which is responsible for C(4)-HSL signal production. Primer extension analysis was used to map the rhlI transcriptional start site and an upstream regulatory region was identified. Expression studies revealed that (i) this regulatory region is important for rhlI expression and (ii) although the rhl QS system will induce rhlI, las is the dominant regulator. Furthermore, we found that control of rhlI in Escherichia coli is markedly different than in P. aeruginosa.}, 
location = {Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.}, 
keywords = {rhlI},}

@Article{Diggle2007,
author = {Diggle, SP and Griffin, AS and Campbell, GS and West, SA}, 
title = {Cooperation and conflict in quorum-sensing bacterial populations.}, 
journal = {Nature}, 
volume = {450}, 
number = {7168}, 
pages = {411--414}, 
year = {2007}, 
abstract = {It has been suggested that bacterial cells communicate by releasing and sensing small diffusible signal molecules in a process commonly known as quorum sensing (QS). It is generally assumed that QS is used to coordinate cooperative behaviours at the population level. However, evolutionary theory predicts that individuals who communicate and cooperate can be exploited. Here we examine the social evolution of QS experimentally in the opportunistic pathogen Pseudomonas aeruginosa, and show that although QS can provide a benefit at the group level, exploitative individuals can avoid the cost of producing the QS signal or of performing the cooperative behaviour that is coordinated by QS, and can therefore spread. We also show that a solution to the problem of exploitation is kin selection, if interacting bacterial cells tend to be close relatives. These results show that the problem of exploitation, which has been the focus of considerable attention in animal communication, also arises in bacteria.}, 
location = {Institute of Infection, Immunity \& Inflammation, Centre for Biomolecular Sciences, University Park, University of Nottingham, Nottingham NG7 2RD, UK. steve.diggle@nottingham.ac.uk}, 
keywords = {lasB, cooperation},}

@Article{Dockery2001,
author = {Dockery, JD and Keener, JP}, 
title = {A mathematical model for quorum sensing in {\emph{Pseudomonas aeruginosa}}}, 
journal = {Bull Math Biol}, 
volume = {63}, 
number = {1}, 
pages = {95--116}, 
year = {2001}, 
abstract = {The bacteria Pseudomonas aeruginosa use the size and density of their colonies to regulate the production of a large variety of substances, including toxins. This phenomenon, called quorum sensing, apparently enables colonies to grow to sufficient size undetected by the immune system of the host organism. In this paper, we present a mathematical model of quorum sensing in P. aeruginosa that is based on the known biochemistry of regulation of the autoinducer that is crucial to this signalling mechanism. Using this model we show that quorum sensing works because of a biochemical switch between two stable steady solutions, one with low levels of autoinducer and one with high levels of autoinducer.}, 
location = {Department of Mathematics, Montana State University, Bozeman, MT 59718, USA. umsfjdoc@math.montana.edu}, }

@Article{Fekete2010,
author = {Fekete, A and Kuttler, C and Rothballer, M and Hense, BA and Fischer, D and Buddrus-Schiemann, K and Lucio, M and Müller, J and Schmitt-Kopplin, P and Hartmann, A}, 
title = {Dynamic regulation of N-acyl-homoserine lactone production and degradation in {\emph{Pseudomonas putida}} IsoF.}, 
journal = {FEMS Microbiol Ecol}, 
volume = {72}, 
number = {1}, 
pages = {22--34}, 
year = {2010}, 
abstract = {The biocontrol strain Pseudomonas putida IsoF, which was isolated from a tomato rhizosphere, is a known N-acyl-homoserine lactone (AHL) producer with only one LuxI/LuxR-like quorum-sensing (QS) system. The production and degradation of AHLs were analysed in different growth phases of the bacterium. Using the analytical tools of ultra performance liquid chromatography and high resolution MS, it was possible to determine not only the various AHLs synthesized over time but also their degradation products. 3-oxo-decanoyl-homoserine lactone was found to be the dominant AHL, which reached its maximum in the early logarithmic growth phase. Although the pH of the medium was neutral, the AHLs were degraded thereafter rapidly to the corresponding homoserines and other metabolites. The proposed lactonase gene of P. putida IsoF could not be identified, because it is apparently quite different from hitherto described lactonases. The analytical data were used to calculate the rates and thresholds of AHL production by mathematical modelling, allowing quantitative predictions and a further understanding of the QS-based regulations in this bacterium. This study, combining microbiological, chemical and mathematical approaches, suggests that AHL degradation is an integral part of the whole autoinducer circuit of P. putida IsoF.}, 
location = {Institute of Ecological Chemistry, Helmholtz Zentrum München, Neuherberg, Germany.}, }

@Article{Fuqua1994,
author = {Fuqua, WC and Winans, SC and Greenberg, EP}, 
title = {Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators.}, 
journal = {J Bacteriol}, 
volume = {176}, 
number = {2}, 
pages = {269--275}, 
year = {1994}, 
location = {Section of Microbiology, Cornell University, Ithaca, New York 14853.}, }

@Article{Hawver2016,
author = {Hawver, LA and Jung, SA and Ng, WL}, 
title = {Specificity and complexity in bacterial quorum-sensing systems.}, 
journal = {FEMS Microbiol Rev}, 
volume = {40}, 
number = {5}, 
pages = {738--752}, 
year = {2016}, 
abstract = {Quorum sensing (QS) is a microbial cell-to-cell communication process that relies on the production and detection of chemical signals called autoinducers (AIs) to monitor cell density and species complexity in the population. QS allows bacteria to behave as a cohesive group and coordinate collective behaviors. While most QS receptors display high specificity to their AI ligands, others are quite promiscuous in signal detection. How do specific QS receptors respond to their cognate signals with high fidelity? Why do some receptors maintain low signal recognition specificity? In addition, many QS systems are composed of multiple intersecting signaling pathways: what are the benefits of preserving such a complex signaling network when a simple linear `one-to-one' regulatory pathway seems sufficient to monitor cell density? Here, we will discuss different molecular mechanisms employed by various QS systems that ensure productive and specific QS responses. Moreover, the network architectures of some well-characterized QS circuits will be reviewed to understand how the wiring of different regulatory components achieves different biological goals.}, 
location = {Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA Wai-Leung.Ng@tufts.edu.}, 
keywords = {crosstalk},}

@Article{Hense2007,
author = {Hense, BA and Kuttler, C and Müller, J and Rothballer, M and Hartmann, A and Kreft, JU}, 
title = {Does efficiency sensing unify diffusion and quorum sensing}, 
journal = {Nat Rev Microbiol}, 
volume = {5}, 
number = {3}, 
pages = {230--239}, 
year = {2007}, 
abstract = {Quorum sensing faces evolutionary problems from non-producing or over-producing cheaters. Such problems are circumvented in diffusion sensing, an alternative explanation for quorum sensing. However, both explanations face the problems of signalling in complex environments such as the rhizosphere where, for example, the spatial distribution of cells can be more important for sensing than cell density, which we show by mathematical modelling. We argue that these conflicting concepts can be unified by a new hypothesis, efficiency sensing, and that some of the problems associated with signalling in complex environments, as well as the problem of maintaining honesty in signalling, can be avoided when the signalling cells grow in microcolonies.}, 
location = {Institute of Biomathematics and Biometry, GSF-National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, D85764 Neuherberg/Munich, Germany. burkhard.hense@gsf.de}, }

@Article{Herzog2019,
author = {Herzog, R and Peschek, N and Fröhlich, KS and Schumacher, K and Papenfort, K}, 
title = {Three autoinducer molecules act in concert to control virulence gene expression in Vibrio cholerae.}, 
journal = {Nucleic Acids Res}, 
volume = {47}, 
number = {6}, 
pages = {3171--3183}, 
year = {2019}, 
abstract = {Bacteria use quorum sensing to monitor cell density and coordinate group behaviours. In Vibrio cholerae, the causative agent of the diarrheal disease cholera, quorum sensing is connected to virulence gene expression via the two autoinducer molecules, AI-2 and CAI-1. Both autoinducers share one signal transduction pathway to control the production of AphA, a key transcriptional activator of biofilm formation and virulence genes. In this study, we demonstrate that the recently identified autoinducer, DPO, also controls AphA production in V. cholerae. DPO, functioning through the transcription factor VqmA and the VqmR small RNA, reduces AphA levels at the post-transcriptional level and consequently inhibits virulence gene expression. VqmR-mediated repression of AphA provides an important link between the AI-2/CAI-1 and DPO-dependent quorum sensing pathways in V. cholerae. Transcriptome analyses comparing the effect of single autoinducers versus autoinducer combinations show that quorum sensing controls the expression of ∼400 genes in V. cholerae and that all three autoinducers are required for a full quorum sensing response. Together, our data provide a global view on autoinducer interplay in V. cholerae and highlight the importance of RNA-based gene control for collective functions in this major human pathogen.}, 
location = {Faculty of Biology I, Department of Microbiology, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany. Munich Center for Integrated Protein Science (CIPSM), Germany. Faculty of Biology I, Department of Microbiology, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany. Faculty of Biology I, Department of Microbiology, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany. Faculty of Biology I, Department of Microbiology, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany. Munich Center for Integrated Protein Science (CIPSM), Germany.}, 
keywords = {repression},}

@Article{James2000,
author = {James, S and Nilsson, P and James, G and Kjelleberg, S and Fagerström, T}, 
title = {Luminescence control in the marine bacterium {\emph{Vibrio fischeri:}} An analysis of the dynamics of lux regulation.}, 
journal = {J Mol Biol}, 
volume = {296}, 
number = {4}, 
pages = {1127--1137}, 
year = {2000}, 
abstract = {A mathematical model has been developed based on the fundamental properties of the control system formed by the lux genes and their products in Vibrio fischeri. The model clearly demonstrates how the components of this system work together to create two, stable metabolic states corresponding to the expression of the luminescent and non-luminescent phenotypes. It is demonstrated how the cell can  between these steady states due to changes in parameters describing metabolic processes and the extracellular concentration of the signal molecule N-3-oxohexanoyl-l-homoserine lactone. In addition, it is shown how these parameters influence how sensitive the switch mechanism is to cellular LuxR and N-3-oxohexanoyl-l-homoserine lactone and complex concentration. While these properties could lead to the collective phenomenon known as quorum sensing, the model also predicts that under certain metabolic circumstances, basal expression of the lux genes could cause a cell to luminesce in the absence of extracellular signal molecule. Finally, the model developed in this study provides a basis for analysing the impact of other levels of control upon lux regulation.}, 
location = {Centre for Marine Biofouling and Bio-innovation, The University of New South Wales, Sydney, 2052, Australia. sally@unsw.edu.au}, }

@Article{Jung2016,
author = {Jung, SA and Hawver, LA and Ng, WL}, 
title = {Parallel quorum sensing signaling pathways in Vibrio cholerae.}, 
journal = {Curr Genet}, 
volume = {62}, 
number = {2}, 
pages = {255--260}, 
year = {2016}, 
abstract = {Quorum sensing (QS) is a microbial signaling process for monitoring population density and complexity. Communication among bacterial cells via QS relies on the production, secretion, and detection of small molecules called autoinducers. Many bacteria have evolved their QS systems with different network architectures to incorporate information from multiple signals. In the human pathogen Vibrio cholerae, at least four parallel signaling pathways converge to control the activity of a single regulator to modulate its QS response. By integrating multiple signal inputs, it is believed that Vibrio species can survey intra-species, intra-genus, and inter-species populations and program their gene expression accordingly. Our recent studies suggest that this  circuitry is also important for maintaining the integrity of the input-output relationship of the system and minimizes premature commitment to QS due to signal perturbation. Here we discuss the implications of this specific parallel network setup for V. cholerae intercellular communication and how this system arrangement affects our approach to manipulate the QS response of this clinically important pathogen.}, 
location = {Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA. Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA. wai-leung.ng@tufts.edu. Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA. wai-leung.ng@tufts.edu.}, 
keywords = {funnel},}

@Article{Kaplan2008,
author = {Kaplan, S and Bren, A and Zaslaver, A and Dekel, E and Alon, U}, 
title = {Diverse two-dimensional input functions control bacterial sugar genes.}, 
journal = {Mol Cell}, 
volume = {29}, 
number = {6}, 
pages = {786--792}, 
year = {2008}, 
abstract = {Cells respond to signals by regulating gene expression. The relation between the level of input signals and the transcription rate of the gene is called the gene's input function. Because most genes are regulated by more than one signal, the input functions are usually multidimensional. To understand cellular responses, it is essential to know the shapes of these functions. Here, we map the two-dimensional input functions of 19 sugar-utilization genes at high resolution in living E. coli cells. We find diverse, intricately shaped input functions, despite the similarity in the regulatory circuitry of these genes. Surprisingly, some of the input functions are nonmonotonic, peaking at intermediate signal levels. Furthermore, most of the input functions show separation of variables, in the sense that they can be described as the product of simple functions that depend on a single input. This first broad survey of two-dimensional input functions can be extended to map the logic of gene regulation in other systems.}, 
location = {Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.}, 
keywords = {logic},}

@Article{Kiratisin2002,
author = {Kiratisin, P and Tucker, KD and Passador, L}, 
title = {LasR, a transcriptional activator of  {\emph{Pseudomonas aeruginosa}} virulence genes, functions as a multimer.}, 
journal = {J Bacteriol}, 
volume = {184}, 
number = {17}, 
pages = {4912--4919}, 
year = {2002}, 
abstract = {The Pseudomonas aeruginosa LasR protein functions in concert with N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C(12)-HSL) to coordinate the expression of target genes, including many genes that encode virulence factors, with cell density. We used a LexA-based protein interaction assay to demonstrate that LasR forms multimers only when 3O-C(12)-HSL is present. A series of LasR molecules containing internal deletions or substitutions in single, conserved amino acid residues indicated that the N-terminal portion of LasR is required for multimerization. Studies performed with these mutant versions of LasR demonstrated that the ability of LasR to multimerize correlates with its ability to function as a transcriptional activator of lasI, a gene known to be tightly regulated by the LasR-3O-C(12)-HSL regulatory system. A LasR molecule that carries a C-terminal deletion can function as a dominant-negative mutant in P. aeruginosa, as shown by its ability to decrease expression of lasB, another LasR-3O-C(12)-HSL target gene. Taken together, our data strongly support the hypothesis that LasR functions as a multimer in vivo.}, 
location = {Department of Microbiology and Immunology, University of Rochester Medical Center, Box 672, Rochester, NY 14642, USA.}, 
keywords = {lasR},}

@Article{Latifi1996,
author = {Latifi, A and Foglino, M and Tanaka, K and Williams, P and Lazdunski, A}, 
title = {A hierarchical quorum-sensing cascade in {\emph{Pseudomonas aeruginosa}} links the transcriptional activators LasR and RhIR (VsmR) to expression of the stationary-phase sigma factor RpoS.}, 
journal = {Mol Microbiol}, 
volume = {21}, 
number = {6}, 
pages = {1137--1146}, 
year = {1996}, 
abstract = {In Pseudomonas aeruginosa, the production of many virulence factors and secondary metabolites is regulated in concert with cell density through quorum sensing. Two quorum-sensing regulons have been identified in which the LuxR homologues LasR and RhlR are activated by N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-butanoyl-L-homoserine lactone (BHL) respectively. The lasR and rhlR genes are linked to the luxl homologues lasl and rhll, which are responsible for synthesis of OdDHL and BHL, respectively. As lasRl and rhlRl are both involved in regulating synthesis of exoenzymes such as elastase, we sought to determine the nature of their interrelationship. By using lacZ transcriptional fusions in both homologous (P. aeruginosa) and heterologous (Escherichia coli) genetic backgrounds we provide evidence that (i) lasR is expressed constitutively throughout the growth cycle, (ii) rhlR expression is regulated by LasR/OdDHL, and (iii) that RhlR/BHL regulates rhll. We also show that expression of the stationary-phase sigma factor gene rpoS is abolished in a P. aeruginosa lasR mutant and in the pleiotropic BHL-negative mutant PANO67. Furthermore, our data reveal that kin E. coli, an rpoS-lacZ fusion is regulated directly by RhlR/BHL. Taken together, these results indicate that P. aeruginosa employs a multilayered hierarchical quorum-sensing cascade involving RhlR/BHL and LasR/OdDHL, interlinked via RpoS, to integrate the regulation of virulence determinants and secondary metabolites with adaptation and survival in the stationary phase.}, 
location = {Laboratoire d'Ingéniérie et Dynamique des Systèmes Membranaires, Centre National de la Recherche Scientifique, Marseille, France.}, 
keywords = {hierarchy},}

@Article{Lazazzera1997,
author = {Lazazzera, BA and Solomon, JM and Grossman, AD}, 
title = {An exported peptide functions intracellularly to contribute to cell density signaling in B. subtilis.}, 
journal = {Cell}, 
volume = {89}, 
number = {6}, 
pages = {917--925}, 
year = {1997}, 
abstract = {Competence development and sporulation in B. subtilis are partly controlled by peptides that accumulate in culture medium as cells grow to high density. We constructed two genes that encode mature forms of two different signaling molecules, the PhrA peptide that stimulates sporulation, and CSF, the competence- and sporulation-stimulating factor. Both pentapeptides are normally produced by secretion and processing of precursor molecules. The mature pentapeptides were functional when expressed inside the cell, indicating that they normally need to be imported to function. Furthermore, at physiological concentrations (10 nM), CSF was transported into the cell by the oligopeptide permease encoded by spo0K (opp). CSF was shown to have at least three different targets corresponding to its three activities: stimulating competence gene expression at low concentrations, and inhibiting competence gene expression and stimulating sporulation at high concentrations.}, 
location = {Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.}, 
keywords = {repression},}

@Article{Lee2015,
author = {Lee, J and Zhang, L}, 
title = {The hierarchy quorum sensing network in {\emph{Pseudomonas aeruginosa}}.}, 
journal = {Protein Cell}, 
volume = {6}, 
number = {1}, 
pages = {26--41}, 
year = {2015}, 
abstract = {Pseudomonas aeruginosa causes severe and persistent infections in immune compromised individuals and cystic fibrosis sufferers. The infection is hard to eradicate as P. aeruginosa has developed strong resistance to most conventional antibiotics. The problem is further compounded by the ability of the pathogen to form biofilm matrix, which provides bacterial cells a protected environment withstanding various stresses including antibiotics. Quorum sensing (QS), a cell density-based intercellular communication system, which plays a key role in regulation of the bacterial virulence and biofilm formation, could be a promising target for developing new strategies against P. aeruginosa infection. The QS network of P. aeruginosa is organized in a multi-layered hierarchy consisting of at least four interconnected signaling mechanisms. Evidence is accumulating that the QS regulatory network not only responds to bacterial population changes but also could react to environmental stress cues. This plasticity should be taken into consideration during exploration and development of anti-QS therapeutics.}, 
location = {Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.}, 
keywords = {hierarchy},}

@Article{Long2009,
author = {Long, T and Tu, KC and Wang, Y and Mehta, P and Ong, NP and Bassler, BL and Wingreen, NS}, 
title = {Quantifying the integration of quorum-sensing signals with single-cell resolution.}, 
journal = {PLoS Biol}, 
volume = {7}, 
number = {3}, 
pages = {e68}, 
year = {2009}, 
abstract = {Cell-to-cell communication in bacteria is a process known as quorum sensing that relies on the production, detection, and response to the extracellular accumulation of signaling molecules called autoinducers. Often, bacteria use multiple autoinducers to obtain information about the vicinal cell density. However, how cells integrate and interpret the information contained within multiple autoinducers remains a mystery. Using single-cell fluorescence microscopy, we quantified the signaling responses to and analyzed the integration of multiple autoinducers by the model quorum-sensing bacterium Vibrio harveyi. Our results revealed that signals from two distinct autoinducers, AI-1 and AI-2, are combined strictly additively in a shared phosphorelay pathway, with each autoinducer contributing nearly equally to the total response. We found a coherent response across the population with little cell-to-cell variation, indicating that the entire population of cells can reliably distinguish several distinct conditions of external autoinducer concentration. We speculate that the use of multiple autoinducers allows a growing population of cells to synchronize gene expression during a series of distinct developmental stages.}, 
location = {Department of Physics, Princeton University, Princeton, NJ, USA.}, 
keywords = {logic},}

@Article{McGrath2004,
author = {McGrath, S and Wade, DS and Pesci, EC}, 
title = {Dueling quorum sensing systems in {\emph{Pseudomonas aeruginosa}} control the production of the Pseudomonas quinolone signal (PQS).}, 
journal = {FEMS Microbiol Lett}, 
volume = {230}, 
number = {1}, 
pages = {27--34}, 
year = {2004}, 
abstract = {The opportunistic human pathogen Pseudomonas aeruginosa regulates the production of numerous virulence factors via the action of two separate but coordinated quorum sensing systems, las and rhl. These systems control the transcription of genes in response to population density through the intercellular signals N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C(12)-HSL) and N-(butanoyl)-L-homoserine lactone (C(4)-HSL). A third P. aeruginosa signal, 2-heptyl-3-hydroxy-4-quinolone [Pseudomonas quinolone signal (PQS)], also plays a significant role in the transcription of multiple P. aeruginosa virulence genes. PQS is intertwined in the P. aeruginosa quorum sensing hierarchy with its production and bioactivity requiring the las and rhl quorum sensing systems, respectively. This report presents a preliminary transcriptional analysis of pqsA, the first gene of the recently discovered PQS biosynthetic gene cluster. We show that pqsA transcription required pqsR, a transcriptional activator protein encoded within the PQS biosynthetic gene cluster. It was also found that the transcription of pqsA and subsequent production of PQS was induced by the las quorum sensing system and repressed by the rhl quorum sensing system. In addition, PQS production was dependent on the ratio of 3-oxo-C(12)-HSL to C(4)-HSL, suggesting a regulatory balance between quorum sensing systems. These data are an important early step toward understanding the regulation of PQS synthesis and the role of PQS in P. aeruginosa intercellular signaling.}, 
location = {Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.}, }

@Article{Medina2003,
author = {Medina, G and Juárez, K and Díaz, R and Soberón-Chávez, G}, 
title = {Transcriptional regulation of {\emph{Pseudomonas aeruginosa}} {\emph{rhlR,}} encoding a quorum-sensing regulatory protein.}, 
journal = {Microbiology (Reading)}, 
volume = {149}, 
number = {Pt 11}, 
pages = {3073--3081}, 
year = {2003}, 
abstract = {The Pseudomonas aeruginosa rhlR gene encodes the transcriptional regulator RhlR which has a central role in the quorum-sensing response. Different gene products involved in bacterial pathogenesis are regulated at the transcriptional level by two quorum-sensing response systems, Las and Rhl. The expression of rhlR has been reported to be under the control of the Las system, but its transcriptional regulation has not been studied in detail. Here, the rhlR promoter region has been characterized and shown to present four different transcription start sites, two of which are included in the upstream gene (rhlB) coding region. It was found that rhlR expression is not only dependent on LasR but also on different regulatory proteins such as Vfr and RhlR itself, and also on the alternative sigma factor sigma(54). It is reported that rhlR expression is partially LasR-independent under certain culture conditions and is strongly influenced by environmental factors.}, 
location = {Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Apdo Postal 510-3, Cuernavaca, Morelos 62250, Mexico. Programa de Ingeniería Metabólica, Centro de Investigación sobre Fijación de Nitrógeno, Universidad Nacional Autónoma de México, Mexico. Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Apdo Postal 510-3, Cuernavaca, Morelos 62250, Mexico.}, }

@Article{Ng2009,
author = {Ng, WL and Bassler, BL}, 
title = {Bacterial quorum-sensing network architectures.}, 
journal = {Annu Rev Genet}, 
volume = {43}, 
pages = {197--222}, 
year = {2009}, 
abstract = {Quorum sensing is a cell-cell communication process in which bacteria use the production and detection of extracellular chemicals called autoinducers to monitor cell population density. Quorum sensing allows bacteria to synchronize the gene expression of the group, and thus act in unison. Here, we review the mechanisms involved in quorum sensing with a focus on the Vibrio harveyi and Vibrio cholerae quorum-sensing systems. We discuss the differences between these two quorum-sensing systems and the differences between them and other paradigmatic bacterial signal transduction systems. We argue that the Vibrio quorum-sensing systems are optimally designed to precisely translate extracellular autoinducer information into internal changes in gene expression. We describe how studies of the V. harveyi and V. cholerae quorum-sensing systems have revealed some of the fundamental mechanisms underpinning the evolution of collective behaviors.}, 
location = {Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA.}, }

@Article{Nouwens2003,
author = {Nouwens, AS and Beatson, SA and Whitchurch, CB and Walsh, BJ and Schweizer, HP and Mattick, JS and Cordwell, SJ}, 
title = {Proteome analysis of extracellular proteins regulated by the {\emph{las}} and {\emph{rhl}} quorum sensing systems in {\emph{Pseudomonas aeruginosa}} PAO1.}, 
journal = {Microbiology (Reading)}, 
volume = {149}, 
number = {Pt 5}, 
pages = {1311--1322}, 
year = {2003}, 
abstract = {The las and rhl quorum sensing (QS) systems regulate the expression of several genes in response to cell density changes in Pseudomonas aeruginosa. Many of these genes encode surface-associated or secreted virulence factors. Proteins from stationary phase culture supernatants were collected from wild-type and P. aeruginosa PAO1 mutants deficient in one or more of the lasRI, rhlRI and vfr genes and analysed using two-dimensional gel electrophoresis. All mutants released significantly lower amounts of protein than the wild-type. Protein spot patterns from each strain were compared using image analysis and visible spot differences were identified using mass spectrometry. Several previously unknown QS-regulated proteins were characterized, including an aminopeptidase (PA2939), an endoproteinase (PrpL) and a unique `hypothetical' protein (PA0572), which could not be detected in the culture supernatants of Deltalas mutants, although they were unaffected in Deltarhl mutants. Chitin-binding protein (CbpD) and a hypothetical protein (PA4944) with similarity to host factor I (HF-I) could not be detected when any of the lasRI or rhlRI genes were disrupted. Fourteen proteins were present at significantly greater levels in the culture supernatants of QS mutants, suggesting that QS may also negatively control the expression of some genes. Increased levels of two-partner secretion exoproteins (PA0041 and PA4625) were observed and may be linked to increased stability of their cognate transporters in a QS-defective background. Known QS-regulated extracellular proteins, including elastase (lasB), LasA protease (lasA) and alkaline metalloproteinase (aprA) were also detected.}, 
location = {Australian Proteome Analysis Facility, Level 4, Building F7B, Macquarie University, Australia 2109. ARC Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, Australia 4072. ARC Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, Australia 4072. Australian Proteome Analysis Facility, Level 4, Building F7B, Macquarie University, Australia 2109. Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523-1677, USA. ARC Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, Australia 4072. Australian Proteome Analysis Facility, Level 4, Building F7B, Macquarie University, Australia 2109.}, }

@Article{Pai2009,
author = {Pai, A and You, L}, 
title = {Optimal tuning of bacterial sensing potential.}, 
journal = {Mol Syst Biol}, 
volume = {5}, 
pages = {286}, 
year = {2009}, 
abstract = {Through production and sensing of small signal molecules, quorum sensing (QS) enables bacteria to detect changes in their density and regulate their functions accordingly. QS systems are tremendously diverse in terms of their specific sensory components, the biochemical and transport properties of signaling molecules, their target functions and the context in which QS-mediated functions are activated. Cutting across this diversity, however, the central architecture of QS systems is universal; it comprises signal synthesis, secretion, degradation and detection. We are thus able to derive a general metric for QS `sensing potential' based on this `core' module. The sensing potential quantifies the ability of a single bacterium to sense the dimensions of its microenvironment. This simple metric captures the dominant activation properties of diverse QS systems, giving a concise description of the sensing characteristics. As such, it provides a convenient quantitative framework to study the phenotypic effects of QS characteristics. As an example, we show how QS characteristics uniquely determine the scenarios in which regulation of a typical QS-controlled function, such as exoenzyme secretion, becomes advantageous.}, 
location = {Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.}, }

@Article{Papenfort2016,
author = {Papenfort, K and Bassler, BL}, 
title = {Quorum sensing signal-response systems in Gram-negative bacteria.}, 
journal = {Nat Rev Microbiol}, 
volume = {14}, 
number = {9}, 
pages = {576--588}, 
year = {2016}, 
abstract = {Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.}, 
location = {Department of Biology, Ludwig-Maximilians-University Munich, Biocenter, 82152 Martinsried, Germany. Howard Hughes Medical Institute; Department of Molecular Biology, 329 Lewis Thomas Laboratories, Washington Road, Princeton University, Princeton, New Jersey 08544, USA.}, }

@Article{Pearson1997,
author = {Pearson, JP and Pesci, EC and Iglewski, BH}, 
title = {Roles of {\emph{Pseudomonas aeruginosa}} {\emph{las}} and {\emph{rhl}} quorum-sensing systems in control of elastase and rhamnolipid biosynthesis genes.}, 
journal = {J Bacteriol}, 
volume = {179}, 
number = {18}, 
pages = {5756--5767}, 
year = {1997}, 
abstract = {Two quorum-sensing systems (las and rhl) regulate virulence gene expression in Pseudomonas aeruginosa. The las system consists of a transcriptional activator, LasR, and LasI, which directs the synthesis of the autoinducer N-(3-oxododecanoyl) homoserine lactone (PAI-1). Induction of lasB (encoding elastase) and other virulence genes requires LasR and PAI-1. The rhl system consists of a putative transcriptional activator, RhlR, and RhlI, which directs the synthesis of N-butyryl homoserine lactone (PAI-2). Rhamnolipid production in P. aeruginosa has been reported to require both the rhl system and rhlAB (encoding a rhamnosyltransferase). Here we report the generation of a delta lasI mutant and both delta lasI delta rhlI and delta lasR rhlR::Tn501 double mutants of strain PAO1. Rhamnolipid production and elastolysis were reduced in the delta lasI single mutant and abolished in the double-mutant strains. rhlAB mRNA was not detected in these strains at mid-logarithmic phase but was abundant in the parental strain. Further RNA analysis of the wild-type strain revealed that rhlAB is organized as an operon. The rhlAB transcriptional start was mapped, and putative sigma 54 and sigma 70 promoters were identified upstream. To define components required for rhlAB expression, we developed a bioassay in Escherichia coli and demonstrated that PAI-2 and RhlR are required and sufficient for expression of rhlA. To characterize the putative interaction between PAI-2 and RhlR, we demonstrated that [3H]PAI-2 binds to E. coli cells expressing RhlR and not to those expressing LasR. Finally, the specificity of the las and rhl systems was examined in E. coli bioassays. The las system was capable of mildly activating rhlA, and similarly, the rhl system partly activated lasB. However; these effects were much less than the activation of rhlA by the rhl system and lasB by the las system. The results presented here further characterize the roles of the rhl and las quorum-sensing systems in virulence gene expression.}, 
location = {Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642, USA.}, 
keywords = {lasB},}

@Article{Pearson1999,
author = {Pearson, JP and Van Delden, C and Iglewski, BH}, 
title = {Active efflux and diffusion are involved in transport of {\emph{Pseudomonas aeruginosa}} cell-to-cell signals.}, 
journal = {J Bacteriol}, 
volume = {181}, 
number = {4}, 
pages = {1203--1210}, 
year = {1999}, 
abstract = {Many gram-negative bacteria communicate by N-acyl homoserine lactone signals called autoinducers (AIs). In Pseudomonas aeruginosa, cell-to-cell signaling controls expression of extracellular virulence factors, the type II secretion apparatus, a stationary-phase sigma factor (sigmas), and biofilm differentiation. The fact that a similar signal, N-(3-oxohexanoyl) homoserine lactone, freely diffuses through Vibrio fischeri and Escherichia coli cells has led to the assumption that all AIs are freely diffusible. In this work, transport of the two P. aeruginosa AIs, N-(3-oxododecanoyl) homoserine lactone (3OC12-HSL) (formerly called PAI-1) and N-butyryl homoserine lactone (C4-HSL) (formerly called PAI-2), was studied by using tritium-labeled signals. When [3H]C4-HSL was added to cell suspensions of P. aeruginosa, the cellular concentration reached a steady state in less than 30 s and was nearly equal to the external concentration, as expected for a freely diffusible compound. In contrast, [3H]3OC12-HSL required about 5 min to reach a steady state, and the cellular concentration was 3 times higher than the external level. Addition of inhibitors of the cytoplasmic membrane proton gradient, such as azide, led to a strong increase in cellular accumulation of [3H]3OC12-HSL, suggesting the involvement of active efflux. A defined mutant lacking the mexA-mexB-oprM-encoded active-efflux pump accumulated [3H]3OC12-HSL to levels similar to those in the azide-treated wild-type cells. Efflux experiments confirmed these observations. Our results show that in contrast to the case for C4-HSL, P. aeruginosa cells are not freely permeable to 3OC12-HSL. Instead, the mexA-mexB-oprM-encoded efflux pump is involved in active efflux of 3OC12-HSL. Apparently the length and/or degree of substitution of the N-acyl side chain determines whether an AI is freely diffusible or is subject to active efflux by P. aeruginosa.}, 
location = {Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA.}, }

@Article{Perez2018,
author = {Pérez-Velázquez, J and Hense, BA}, 
title = {Differential Equations Models to Study Quorum Sensing.}, 
journal = {Methods Mol Biol}, 
volume = {1673}, 
pages = {253--271}, 
year = {2018}, 
abstract = {Mathematical models to study quorum sensing (QS) have become an important tool to explore all aspects of this type of bacterial communication. A wide spectrum of mathematical tools and methods such as dynamical systems, stochastics, and spatial models can be employed. In this chapter, we focus on giving an overview of models consisting of differential equations (DE), which can be used to describe changing quantities, for example, the dynamics of one or more signaling molecule in time and space, often in conjunction with bacterial growth dynamics. The chapter is divided into two sections: ordinary differential equations (ODE) and partial differential equations (PDE) models of QS. Rates of change are represented mathematically by derivatives, i.e., in terms of DE. ODE models allow describing changes in one independent variable, for example, time. PDE models can be used to follow changes in more than one independent variable, for example, time and space. Both types of models often consist of systems (i.e., more than one equation) of equations, such as equations for bacterial growth and autoinducer concentration dynamics. Almost from the onset, mathematical modeling of QS using differential equations has been an interdisciplinary endeavor and many of the works we revised here will be placed into their biological context.}, 
location = {Mathematical Modeling of Biological Systems, Centre for Mathematical Science, Technical University of Munich, Garching, Germany. perez-velazquez@helmholtz-muenchen.de. Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. perez-velazquez@helmholtz-muenchen.de. Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.}, }

@Article{Perez2011,
author = {Pérez, PD and Weiss, JT and Hagen, SJ}, 
title = {Noise and crosstalk in two quorum-sensing inputs of Vibrio fischeri.}, 
journal = {BMC Syst Biol}, 
volume = {5}, 
pages = {153}, 
year = {2011}, 
abstract = {BACKGROUND:  One of the puzzles in bacterial quorum sensing is understanding how an organism integrates the information gained from multiple input signals. The marine bacterium Vibrio fischeri regulates its bioluminescence through a quorum sensing mechanism that receives input from three pheromone signals, including two acyl homoserine lactone (HSL) signals. While the role of the 3-oxo-C6 homoserine lactone (3OC6HSL) signal in activating the lux genes has been extensively studied and modeled, the role of the C8 homoserine lactone (C8HSL) is less obvious, as it can either activate luminescence or block its activation. It remains unclear how crosstalk between C8HSL and 3OC6HSL affects the information that the bacterium obtains through quorum sensing. RESULTS:  We have used microfluidic methods to measure the response of individual V.fischeri cells to combinations of C8HSL and 3OC6HSL. By measuring the fluorescence of individual V.fischeri cells containing a chromosomal gfp-reporter for the lux genes, we study how combinations of exogenous HSLs affect both the population average and the cell-to-cell variability of lux activation levels. At the level of a population average, the crosstalk between the C8HSL and 3OC6HSL inputs is well-described by a competitive inhibition model. At the level of individual cells, the heterogeneity in the lux response depends only on the average degree of activation, so that the noise in the output is not reduced by the presence of the second HSL signal. Overall we find that the mutual information between the signal inputs and the lux output is less than one bit. A nonlinear correlation between fluorescence and bioluminescence outputs from lux leads to different noise properties for these reporters. CONCLUSIONS:  The lux genes in V.fischeri do not appear to distinguish between the two HSL inputs, and even with two signal inputs the regulation of lux is extremely noisy. Hence the role of crosstalk from the C8HSL input may not be to improve sensing precision, but rather to suppress the sensitivity of the switch for as long as possible during colony growth.}, 
location = {Department of Physics, University of Florida, Gainesville, FL 32611-8440, USA.}, 
keywords = {crosstalk},}

@Article{Pesci1999,
author = {Pesci, EC and Milbank, JB and Pearson, JP and McKnight, S and Kende, AS and Greenberg, EP and Iglewski, BH}, 
title = {Quinolone signaling in the cell-to-cell communication system of {\emph{Pseudomonas aeruginosa}}}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {96}, 
number = {20}, 
pages = {11229--11234}, 
year = {1999}, 
abstract = {Numerous species of bacteria use an elegant regulatory mechanism known as quorum sensing to control the expression of specific genes in a cell-density dependent manner. In Gram-negative bacteria, quorum sensing systems function through a cell-to-cell signal molecule (autoinducer) that consists of a homoserine lactone with a fatty acid side chain. Such is the case in the opportunistic human pathogen Pseudomonas aeruginosa, which contains two quorum sensing systems (las and rhl) that operate via the autoinducers, N-(3-oxododecanoyl)-L-homoserine lactone and N-butyryl-L-homoserine lactone. The study of these signal molecules has shown that they bind to and activate transcriptional activator proteins that specifically induce numerous P. aeruginosa virulence genes. We report here that P. aeruginosa produces another signal molecule, 2-heptyl-3-hydroxy-4-quinolone, which has been designated as the Pseudomonas quinolone signal. It was found that this unique cell-to-cell signal controlled the expression of lasB, which encodes for the major virulence factor, LasB elastase. We also show that the synthesis and bioactivity of Pseudomonas quinolone signal were mediated by the P. aeruginosa las and rhl quorum sensing systems, respectively. The demonstration that 2-heptyl-3-hydroxy-4-quinolone can function as an intercellular signal sheds light on the role of secondary metabolites and shows that P. aeruginosa cell-to-cell signaling is not restricted to acyl-homoserine lactones.}, 
location = {Department of Microbiology, East Carolina University School of Medicine, Greenville, NC 27858, USA. epesci@brody.med.ecu.edu}, }

@Article{Pesci1997,
author = {Pesci, EC and Pearson, JP and Seed, PC and Iglewski, BH}, 
title = {Regulation of {\emph{las}} and {\emph{rhl}} quorum sensing in {\emph{Pseudomonas aeruginosa}}}, 
journal = {J Bacteriol}, 
volume = {179}, 
number = {10}, 
pages = {3127--3132}, 
year = {1997}, 
abstract = {The production of several virulence factors by Pseudomonas aeruginosa is controlled according to cell density through two quorum-sensing systems, las and rhl. The las system is comprised of the transcriptional activator protein LasR and of LasI, which directs the synthesis of the autoinducer PAI-1. Similarly, the rhl system consists of the transcriptional activator protein RhlR and of RhlI, which directs synthesis of the autoinducer PAI-2 (formerly referred to as factor 2). To study the interrelation between the two P. aeruginosa quorum-sensing systems, we fused a lacZ reporter gene to lasR, rhlR, and rhlA and monitored expression of these three genes under various conditions. Our data indicate that lasR and rhlR are expressed in a growth-dependent manner, with activation of each gene occurring during the last half of log-phase growth. We also show that the las quorum-sensing system controls the rhl quorum-sensing system in two ways. First, we found that LasR and PAI-1 activated rhlR transcription. Second, we showed that PAI-1 blocked PAI-2 from binding to RhlR, thereby inhibiting the expression of rhlA. Our data thus indicate that the las system exerts two levels of control on RhlR, transcriptional and posttranslational.}, 
location = {Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642, USA.}, 
keywords = {hierarchy},}

@Article{Popat2015,
author = {Popat, R and Cornforth, DM and McNally, L and Brown, SP}, 
title = {Collective sensing and collective responses in quorum-sensing bacteria.}, 
journal = {J R Soc Interface}, 
volume = {12}, 
number = {103}, 
pages = {20140882}, 
year = {2015}, 
abstract = {Bacteria often face fluctuating environments, and in response many species have evolved complex decision-making mechanisms to match their behaviour to the prevailing conditions. Some environmental cues provide direct and reliable information (such as nutrient concentrations) and can be responded to individually. Other environmental parameters are harder to infer and require a collective mechanism of sensing. In addition, some environmental challenges are best faced by a group of cells rather than an individual. In this review, we discuss how bacteria sense and overcome environmental challenges as a group using collective mechanisms of sensing, known as `quorum sensing' (QS). QS is characterized by the release and detection of small molecules, potentially allowing individuals to infer environmental parameters such as density and mass transfer. While a great deal of the molecular mechanisms of QS have been described, there is still controversy over its functional role. We discuss what QS senses and how, what it controls and why, and how social dilemmas shape its evolution. Finally, there is a growing focus on the use of QS inhibitors as antibacterial chemotherapy. We discuss the claim that such a strategy could overcome the evolution of resistance. By linking existing theoretical approaches to data, we hope this review will spur greater collaboration between experimental and theoretical researchers.}, 
location = {Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK roman.popat@ed.ac.uk. Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK Molecular Biosciences, University of Texas at Austin, 2500 Speedway NMS 3.254, Austin, TX 78712, USA. Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK. Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK.}, }

@Article{Powell1968,
author = {Powell, Michael JD}, 
title = {A Fortran subroutine for solving systems of nonlinear algebraic equations}, 
year = {1968}, 
abstract = {A Fortran subroutine is described and listed for solving a system of non-linear algebraic equations. The method used to obtain the solution to the equations is a compromise between the Newton-Raphson algorithm and the method of steepest descents applied to minimize the function noted, for the aim is to combine a fast rate of convergence with steady progress. Some examples illustrate the technique, and they indicate that the given algorithm compares favorable with other numerical methods for solving non-linear equations.}, }

@Book{Ratkowsky1983,
author = {Ratkowsky, David A.}, 
title = {Nonlinear Regression Modeling: A Unified Practical Approach}, 
pages = {296}, 
publisher = {Marcel Dekker Incorporated}, 
year = {1983}, 
abstract = {Introduction to regression models; Assessing nonlinearity in nonlinear regression models; Yield-density models; Sigmoidal growth models; Asymptotic regression model; Some miscellaneous models; Comparing parameter estimates from more than one data set; Obtaining good initial parameter estimates; Summary: towatd a unified approach to nonlinear regression modeling.}, 
keywords = {Mathematics},}

@Article{Rattray2022,
author = {Rattray, JB and Thomas, SA and Wang, Y and Molotkova, E and Gurney, J and Varga, JJ and Brown, SP}, 
title = {Bacterial Quorum Sensing Allows Graded and Bimodal Cellular Responses to Variations in Population Density.}, 
journal = {mBio}, 
volume = {13}, 
number = {3}, 
pages = {e0074522}, 
year = {2022}, 
abstract = {Quorum sensing (QS) is a mechanism of cell-cell communication that connects gene expression to environmental conditions (e.g., cell density) in many bacterial species, mediated by diffusible signal molecules. Current functional studies focus on qualitatively distinct QS ON/OFF states. In the context of density sensing, this view led to the adoption of a  analogy in which populations sense when they are above a sufficient density (i.e., ) to efficiently turn on cooperative behaviors. This framework overlooks the potential for intermediate, graded responses to shifts in the environment. In this study, we tracked QS-regulated protease (lasB) expression and showed that Pseudomonas aeruginosa can deliver a graded behavioral response to fine-scale variation in population density, on both the population and single-cell scales. On the population scale, we saw a graded response to variation in population density (controlled by culture carrying capacity). On the single-cell scale, we saw significant bimodality at higher densities, with separate OFF and ON subpopulations that responded differentially to changes in density: a static OFF population of cells and increasing intensity of expression among the ON population of cells. Together, these results indicate that QS can tune gene expression to graded environmental change, with no critical cell mass or  at which behavioral responses are activated on either the individual-cell or population scale. In an infection context, our results indicate there is not a hard threshold separating a quorate  mode from a subquorate  mode. IMPORTANCE Bacteria can be highly social, controlling collective behaviors via cell-cell communication mechanisms known as quorum sensing (QS). QS is now a large research field, yet a basic question remains unanswered: what is the environmental resolution of QS? The notion of a threshold, or  separating coordinated ON and OFF states is a central dogma in QS, but recent studies have shown heterogeneous responses at a single cell scale. Using Pseudomonas aeruginosa, we showed that populations generate graded responses to environmental variation through shifts in the proportion of cells responding and the intensity of responses. In an infection context, our results indicate that there is not a hard threshold separating a quorate  mode and a subquorate  mode.}, 
location = {School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Graduate Program in Quantitative Biosciences (QBioS), Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. The Institute for Data Engineering and Science (IDEaS), Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. School of Biological Sciences, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA. Center for Microbial Dynamics and Infection, Georgia Institute of Technologygrid.213917.f, Atlanta, Georgia, USA.}, }

@Article{Redfield2002,
author = {Redfield, RJ}, 
title = {Is quorum sensing a side effect of diffusion sensing}, 
journal = {Trends Microbiol}, 
volume = {10}, 
number = {8}, 
pages = {365--370}, 
year = {2002}, 
abstract = {Many bacteria appear to communicate by releasing and sensing autoinducer molecules, which are believed to function primarily as sensors of population density. However, this quorum-sensing hypothesis rests on very weak foundations, as neither the need for group action nor the selective conditions required for its evolution have been demonstrated. Here, I argue for a more direct function of autoinducer secretion and response - the ability to determine whether secreted molecules rapidly move away from the cell. This diffusion sensing allows cells to regulate secretion of degradative enzymes and other effectors to minimize losses owing to extracellular diffusion and mixing.}, 
location = {Dept of Zoology, University of British Columbia, Vancouver, BC, Canada. redfield@interchange.ubc.ca}, }

@Article{Santillán2008,
author = {Santillán, Moises}, 
title = {On the use of the Hill functions in mathematical models of gene regulatory networks}, 
journal = {Mathematical Modelling of Natural Phenomena}, 
volume = {3}, 
number = {2}, 
pages = {85--97}, 
year = {2008}, 
abstract = {Hill functions follow from the equilibrium state of the reaction in which n ligands simultaneously bind a single receptor. This result if often employed to interpret the Hill coefficient as the number of ligand binding sites in all kinds of reaction schemes. Here, we study the equilibrium states of the reactions in which n ligand bind a receptor sequentially, both non-cooperatively and in a cooperative fashion. The main outcomes of such analysis are that: n is not a good estimate, but only an upper bound, for the Hill coefficient; while the …}, 
keywords = {hill},}

@Article{Sauer1995,
author = {Sauer, F and Hansen, SK and Tjian, R}, 
title = {Multiple TAFIIs directing synergistic activation of transcription.}, 
journal = {Science}, 
volume = {270}, 
number = {5243}, 
pages = {1783--1788}, 
year = {1995}, 
abstract = {Coordinate activation of transcription by multiple enhancer binding factors is essential for the regulation of pattern formation during development of Drosophila melanogaster. Cell-free transcription reactions are described that recapitulate transcriptional synergism directed by the Drosophila developmental regulators Bicoid (BCD) and Hunchback (HB). Within the basal transcription factor complex TFIID, two specific targets, TAFII110 and TAFII60, served as coactivators to mediate transcriptional activation by these two enhancer binding proteins. A quadruple complex containing TATA binding protein (TBP), TAFII250, TAFII110, and TAFII60 mediated transcriptional synergism by BCD and HB, whereas triple TBP-TAFII complexes lacking one or the other target coactivator failed to support synergistic activation. Deoxyribonuclease I footprint protection experiments revealed that an integral step leading to transcriptional synergism involves the recruitment of TBP-TAFII complexes to the promoter by way of multivalent contacts between activators and selected TAFIIs. Thus, the concerted action of multiple regulators with different coactivators helps to establish the pattern and level of segmentation gene transcription during Drosophila development.}, }

@Article{Schuster2007,
author = {Schuster, M and Greenberg, EP}, 
title = {Early activation of quorum sensing in {\emph{Pseudomonas aeruginosa}} reveals the architecture of a complex regulon.}, 
journal = {BMC Genomics}, 
volume = {8}, 
pages = {287}, 
year = {2007}, 
abstract = {BACKGROUND:  Quorum-sensing regulation of gene expression in Pseudomonas aeruginosa is complex. Two interconnected acyl-homoserine lactone (acyl-HSL) signal-receptor pairs, 3-oxo-dodecanoyl-HSL-LasR and butanoyl-HSL-RhlR, regulate more than 300 genes. The induction of most of the genes is delayed during growth of P. aeruginosa in complex medium, cannot be advanced by addition of exogenous signal, and requires additional regulatory components. Many of these late genes can be induced by addition of signals early by using specific media conditions. While several factors super-regulate the quorum receptors, others may co-regulate target promoters or may affect expression posttranscriptionally. RESULTS:  To better understand the contributions of super-regulation and co-regulation to quorum-sensing gene expression, and to better understand the general structure of the quorum sensing network, we ectopically expressed the two receptors (in the presence of their cognate signals) and another component that affects quorum sensing, the stationary phase sigma factor RpoS, early in growth. We determined the effect on target gene expression by microarray and real-time PCR analysis. Our results show that many target genes (e.g. lasB and hcnABC) are directly responsive to receptor protein levels. Most genes (e.g. lasA, lecA, and phnAB), however, are not significantly affected, although at least some of these genes are directly regulated by quorum sensing. The majority of promoters advanced by RhlR appeared to be regulated directly, which allowed us to build a RhlR consensus sequence. CONCLUSION:  The direct responsiveness of many quorum sensing target genes to receptor protein levels early in growth confirms the role of super-regulation in quorum sensing gene expression. The observation that the induction of most target genes is not affected by signal or receptor protein levels indicates that either target promoters are co-regulated by other transcription factors, or that expression is controlled posttranscriptionally. This architecture permits the integration of multiple signaling pathways resulting in quorum responses that require a  but are otherwise highly adaptable and receptive to environmental conditions.}, 
location = {Department of Microbiology, University of Washington, Box 357242, 1959 NE Pacific St, Seattle, WA 98195, USA. martin.schuster@oregonstate.edu}, }

@Article{Sexton2017,
author = {Sexton, DJ and Schuster, M}, 
title = {Nutrient limitation determines the fitness of cheaters in bacterial siderophore cooperation.}, 
journal = {Nat Commun}, 
volume = {8}, 
number = {1}, 
pages = {230}, 
year = {2017}, 
abstract = {Cooperative behaviors provide a collective benefit, but are considered costly for the individual. Here, we report that these costs vary dramatically in different contexts and have opposing effects on the selection for non-cooperating cheaters. We investigate a prominent example of bacterial cooperation, the secretion of the peptide siderophore pyoverdine by Pseudomonas aeruginosa, under different nutrient-limiting conditions. Using metabolic modeling, we show that pyoverdine incurs a fitness cost only when its building blocks carbon or nitrogen are growth-limiting and are diverted from cellular biomass production. We confirm this result experimentally with a continuous-culture approach. We show that pyoverdine non-producers (cheaters) enjoy a large fitness advantage in co-culture with producers (cooperators) and spread to high frequency when limited by carbon, but not when limited by phosphorus. The principle of nutrient-dependent fitness costs has implications for the stability of cooperation in pathogenic and non-pathogenic environments, in biotechnological applications, and beyond the microbial realm.Cooperative behaviour among individuals provides a collective benefit, but is considered costly. Using Pseudomonas aeruginosa as a model system, the authors show that secretion of the siderophore pyoverdine only incurs a fitness cost and favours cheating when its building blocks carbon or nitrogen are growth-limiting.}, 
location = {Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA. Department of Microbiology, Oregon State University, 226 Nash Hall, Corvallis, OR, 97331, USA. martin.schuster@oregonstate.edu.}, 
keywords = {lasB, cooperation},}

@Article{Stearns1989,
author = {Stearns, SC}, 
title = {The evolutionary significance of phenotypic plasticity}, 
journal = {Bioscience}, 
year = {1989}, 
abstract = {Stephen C. Steams ariation, the fuel that feeds evolutionary change, origi-nates at the levels of both the genotype and the phenotype. Geneti-cally identical organisms reared under different conditions may display quite distinct characteristics. Until recently, the types and sources of such phenotypic variation have been given little consideration in evolutionary theory. But a knowledge of the mechanisms and developmental patterns underlying phenotypic variation is crucial to the understanding of important evo-lutionary phenomena …}, }

@Article{Syed2023,
author = {Syed, S and Duan, Y and Lim, B}, 
title = {Modulation of protein-DNA binding reveals mechanisms of spatiotemporal gene control in early Drosophila embryos.}, 
journal = {Elife}, 
volume = {12}, 
pages = {e85997}, 
year = {2023}, 
abstract = {It is well known that enhancers regulate the spatiotemporal expression of their target genes by recruiting transcription factors (TFs) to the cognate binding sites in the region. However, the role of multiple binding sites for the same TFs and their specific spatial arrangement in determining the overall competency of the enhancer has yet to be fully understood. In this study, we utilized the MS2-MCP live imaging technique to quantitatively analyze the regulatory logic of the snail distal enhancer in early Drosophila embryos. Through systematic modulation of Dorsal and Twist binding motifs in this enhancer, we found that a mutation in any one of these binding sites causes a drastic reduction in transcriptional amplitude, resulting in a reduction in mRNA production of the target gene. We provide evidence of synergy, such that multiple binding sites with moderate affinities cooperatively recruit more TFs to drive stronger transcriptional activity than a single site. Moreover, a Hidden Markov-based stochastic model of transcription reveals that embryos with mutated binding sites have a higher probability of returning to the inactive promoter state. We propose that TF-DNA binding regulates spatial and temporal gene expression and drives robust pattern formation by modulating transcriptional kinetics and tuning bursting rates.}, 
location = {Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, United States. Master of Biotechnology Program, University of Pennsylvania, Philadelphia, United States. Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, United States.}, }

@Article{Wang2013,
author = {Wang, Y and Wang, H and Liang, W and Hay, AJ and Zhong, Z and Kan, B and Zhu, J}, 
title = {Quorum sensing regulatory cascades control Vibrio fluvialis pathogenesis.}, 
journal = {J Bacteriol}, 
volume = {195}, 
number = {16}, 
pages = {3583--3589}, 
year = {2013}, 
abstract = {Quorum sensing (QS) is a process by which individual bacteria are able to communicate with one another, thereby enabling the population as a whole to coordinate gene regulation and subsequent phenotypic outcomes. Communication is accomplished through production and detection of small molecules in the extracellular milieu. In many bacteria, particularly Vibrio species, multiple QS systems result in multiple signals, as well as cross talk between systems. In this study, we identify two QS systems in the halophilic enteric pathogen Vibrio fluvialis: one acyl-homoserine lactone (AHL) based and one CAI-1/AI-2 based. We show that a LuxI homolog, VfqI, primarily produces 3-oxo-C10-HSL, which is sensed by a LuxR homolog, VfqR. VfqR-AHL is required to activate vfqI expression and autorepress vfqR expression. In addition, we have shown that similar to that in V. cholerae and V. harveyi, V. fluvialis produces CAI-1 and AI-2 signal molecules to activate the expression of a V. cholerae HapR homolog through LuxO. Although VfqR-AHL does not regulate hapR expression, HapR can repress vfqR transcription. Furthermore, we found that QS in V. fluvialis positively regulates production of two potential virulence factors, an extracellular protease and hemolysin. QS also affects cytotoxic activity against epithelial tissue cultures. These data suggest that V. fluvialis integrates QS regulatory pathways to play important physiological roles in pathogenesis.}, 
location = {State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.}, 
keywords = {repression},}

@Article{Ward2001,
author = {Ward, JP and King, JR and Koerber, AJ and Williams, P and Croft, JM and Sockett, RE}, 
title = {Mathematical modelling of quorum sensing in bacteria.}, 
journal = {IMA J Math Appl Med Biol}, 
volume = {18}, 
number = {3}, 
pages = {263--292}, 
year = {2001}, 
abstract = {The regulation of density-dependent behaviour by means of quorum sensing is widespread in bacteria, the relevant phenomena including bioluminescence and population expansion by swarming, as well as virulence. The process of quorum sensing is regulated by the production and monitoring of certain molecules (referred to as QSMs); on reaching an apparent threshold concentration of QSMs (reflecting high bacterial density) the bacterial colony in concert `switches on' the density-dependent trait. In this paper a mathematical model which describes bacterial population growth and quorum sensing in a well mixed system is proposed and studied. We view the population of bacteria as consisting of down-regulated and up-regulated sub-populations, with QSMs being produced at a much faster rate by the up-regulated cells. Using curve fitting techniques for parameter estimation, solutions of the resulting system of ordinary differential equations are shown to agree well with experimental data. Asymptotic analysis in a biologically relevant limit is used to investigate the timescales for up-regulation of an exponentially growing population of bacteria, revealing the existence of bifurcation between limited and near-total up-regulation. For a fixed population of cells steady-state analysis reveals that in general one physical steady-state solution exists and is linearly stable; we believe this solution to be a global attractor. A bifurcation between limited and near-total up-regulation is also discussed in the steady-state limit.}, 
location = {Division of Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, UK. john.ward@nottingham.ac.uk}, }

@Article{Wargo2007,
author = {Wargo, MJ and Hogan, DA}, 
title = {Examination of {\emph{Pseudomonas aeruginosa}} {\emph{lasI}} regulation and 3-oxo-C12-homoserine lactone production using a heterologous {\emph{Escherichia coli}} system.}, 
journal = {FEMS Microbiol Lett}, 
volume = {273}, 
number = {1}, 
pages = {38--44}, 
year = {2007}, 
abstract = {In Pseudomonas aeruginosa, the signaling molecule 3-oxo-C12-homoserine lactone (3OC12HSL) is synthesized by LasI, and lasI transcription is positively regulated by LasR. A heterologous model has been generated for the study of the LasRI/3OC12HSL regulatory network in Escherichia coli. Escherichia coli pAHL-BAC cultures produced LasI-synthesized acylhomoserine lactones (AHLs) at levels and with kinetics similar to what is observed in cultures of P. aeruginosa strain PAO1. Analysis of the lasI transcript also showed similar induction profiles in both the E. coli pAHL-BAC strain and P. aeruginosa. Transposon mutagenesis of pAHL-BAC confirmed that transcriptional regulation by LasR is necessary for 3OC12HSL production, and showed that artificially increasing lasI transcript levels leads to higher levels of 3OC12HSL. Previous studies have shown that P. aeruginosa 3OC12HSL inhibits hypha formation, but not growth, in Candida albicans, and the E. coli pAHL-BAC similarly inhibited filamentation when grown in coculture with the fungus. It is proposed that this system will be useful for the study of factors that impact lasI regulation and 3OC12HSL production, and for the examination of the role of LasI-produced AHLs in bacterial interactions with other organisms.}, 
location = {Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755, USA.}, 
keywords = {lasI},}

@Article{Waters2005,
author = {Waters, CM and Bassler, BL}, 
title = {Quorum sensing: cell-to-cell communication in bacteria.}, 
journal = {Annu Rev Cell Dev Biol}, 
volume = {21}, 
pages = {319--346}, 
year = {2005}, 
abstract = {Bacteria communicate with one another using chemical signal molecules. As in higher organisms, the information supplied by these molecules is critical for synchronizing the activities of large groups of cells. In bacteria, chemical communication involves producing, releasing, detecting, and responding to small hormone-like molecules termed autoinducers . This process, termed quorum sensing, allows bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to changes in the number and/or species present in a community. Most quorum-sensing-controlled processes are unproductive when undertaken by an individual bacterium acting alone but become beneficial when carried out simultaneously by a large number of cells. Thus, quorum sensing confuses the distinction between prokaryotes and eukaryotes because it enables bacteria to act as multicellular organisms. This review focuses on the architectures of bacterial chemical communication networks; how chemical information is integrated, processed, and transduced to control gene expression; how intra- and interspecies cell-cell communication is accomplished; and the intriguing possibility of prokaryote-eukaryote cross-communication.}, 
location = {Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA. cwaters@molbio.princeton.edu}, }

@Article{Whiteley2017,
author = {Whiteley, M and Diggle, SP and Greenberg, EP}, 
title = {Progress in and promise of bacterial quorum sensing research.}, 
journal = {Nature}, 
volume = {551}, 
number = {7680}, 
pages = {313--320}, 
year = {2017}, 
abstract = {This Review highlights how we can build upon the relatively new and rapidly developing field of research into bacterial quorum sensing (QS). We now have a depth of knowledge about how bacteria use QS signals to communicate with each other and to coordinate their activities. In recent years there have been extraordinary advances in our understanding of the genetics, genomics, biochemistry, and signal diversity of QS. We are beginning to understand the connections between QS and bacterial sociality. This foundation places us at the beginning of a new era in which researchers will be able to work towards new medicines to treat devastating infectious diseases, and use bacteria to understand the biology of sociality.}, 
location = {School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, USA. Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-7735, USA. Integrative Microbiology Research Center, South China Agricultural University, Guangzhou, China.}, }

@Article{Whiteley1999,
author = {Whiteley, M and Lee, KM and Greenberg, EP}, 
title = {Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {96}, 
number = {24}, 
pages = {13904--13909}, 
year = {1999}, 
abstract = {Bacteria communicate with each other to coordinate expression of specific genes in a cell density-dependent fashion, a phenomenon called quorum sensing and response. Although we know that quorum sensing via acyl-homoserine lactone (HSL) signals controls expression of several virulence genes in the human pathogen Pseudomonas aeruginosa, the number and types of genes controlled by quorum sensing have not been studied systematically. We have constructed a library of random insertions in the chromosome of a P. aeruginosa acyl-HSL synthesis mutant by using a transposon containing a promoterless lacZ. This library was screened for acyl-HSL induction of lacZ. Thirty-nine quorum sensing-regulated genes were identified. The genes were organized into classes depending on the pattern of regulation. About half of the genes appear to be in seven operons, some seem organized in large patches on the genome. Many of the quorum sensing-regulated genes code for putative virulence factors or production of secondary metabolites. Many of the genes identified showed a high level of induction by acyl-HSL signaling.}, 
location = {Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.}, }

@Article{Mayer2023,
author = {Mayer, C and Borges, A and Flament-Simon, SC and Simões, M}, 
title = {Quorum sensing architecture network in Escherichia coli virulence and pathogenesis.}, 
journal = {FEMS Microbiol Rev}, 
volume = {47}, 
number = {4}, 
pages = {fuad031}, 
year = {2023}, 
abstract = {Escherichia coli is a Gram-negative commensal bacterium of the normal microbiota of humans and animals. However, several E. coli strains are opportunistic pathogens responsible for severe bacterial infections, including gastrointestinal and urinary tract infections. Due to the emergence of multidrug-resistant serotypes that can cause a wide spectrum of diseases, E. coli is considered one of the most troublesome human pathogens worldwide. Therefore, a more thorough understanding of its virulence control mechanisms is essential for the development of new anti-pathogenic strategies. Numerous bacteria rely on a cell density-dependent communication system known as quorum sensing (QS) to regulate several bacterial functions, including the expression of virulence factors. The QS systems described for E. coli include the orphan SdiA regulator, an autoinducer-2 (AI-2), an autoinducer-3 (AI-3) system, and indole, which allow E. coli to establish different communication processes to sense and respond to the surrounding environment. This review aims to summarise the current knowledge of the global QS network in E. coli and its influence on virulence and pathogenesis. This understanding will help to improve anti-virulence strategies with the E. coli QS network in focus.}, 
location = {LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal. Laboratorio de Referencia de E. coli, FIDIS-Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain. LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal. ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal. Laboratorio de Referencia de E. coli, FIDIS-Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain. LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal. ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.}, }

@Article{Henke2004,
author = {Henke, JM and Bassler, BL}, 
title = {Three parallel quorum-sensing systems regulate gene expression in Vibrio harveyi.}, 
journal = {J Bacteriol}, 
volume = {186}, 
number = {20}, 
pages = {6902--6914}, 
year = {2004}, 
abstract = {In a process called quorum sensing, bacteria communicate using extracellular signal molecules termed autoinducers. Two parallel quorum-sensing systems have been identified in the marine bacterium Vibrio harveyi. System 1 consists of the LuxM-dependent autoinducer HAI-1 and the HAI-1 sensor, LuxN. System 2 consists of the LuxS-dependent autoinducer AI-2 and the AI-2 detector, LuxPQ. The related bacterium, Vibrio cholerae, a human pathogen, possesses System 2 (LuxS, AI-2, and LuxPQ) but does not have obvious homologues of V. harveyi System 1. Rather, System 1 of V. cholerae is made up of the CqsA-dependent autoinducer CAI-1 and a sensor called CqsS. Using a V. cholerae CAI-1 reporter strain we show that many other marine bacteria, including V. harveyi, produce CAI-1 activity. Genetic analysis of V. harveyi reveals cqsA and cqsS, and phenotypic analysis of V. harveyi cqsA and cqsS mutants shows that these functions comprise a third V. harveyi quorum-sensing system that acts in parallel to Systems 1 and 2. Together these communication systems act as a three-way coincidence detector in the regulation of a variety of genes, including those responsible for bioluminescence, type III secretion, and metalloprotease production.}, 
location = {Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.}, }

@Article{Bridges2019,
author = {Bridges, AA and Bassler, BL}, 
title = {The intragenus and interspecies quorum-sensing autoinducers exert distinct control over Vibrio cholerae biofilm formation and dispersal.}, 
journal = {PLoS Biol}, 
volume = {17}, 
number = {11}, 
pages = {e3000429}, 
year = {2019}, 
abstract = {Vibrio cholerae possesses multiple quorum-sensing (QS) systems that control virulence and biofilm formation among other traits. At low cell densities, when QS autoinducers are absent, V. cholerae forms biofilms. At high cell densities, when autoinducers have accumulated, biofilm formation is repressed, and dispersal occurs. Here, we focus on the roles of two well-characterized QS autoinducers that function in parallel. One autoinducer, called cholerae autoinducer-1 (CAI-1), is used to measure Vibrio abundance, and the other autoinducer, called autoinducer-2 (AI-2), is widely produced by different bacterial species and presumed to enable V. cholerae to assess the total bacterial cell density of the vicinal community. The two V. cholerae autoinducers funnel information into a shared signal relay pathway. This feature of the QS system architecture has made it difficult to understand how specific information can be extracted from each autoinducer, how the autoinducers might drive distinct output behaviors, and, in turn, how the bacteria use QS to distinguish kin from nonkin in bacterial communities. We develop a live-cell biofilm formation and dispersal assay that allows examination of the individual and combined roles of the two autoinducers in controlling V. cholerae behavior. We show that the QS system works as a coincidence detector in which both autoinducers must be present simultaneously for repression of biofilm formation to occur. Within that context, the CAI-1 QS pathway is activated when only a few V. cholerae cells are present, whereas the AI-2 pathway is activated only at much higher cell density. The consequence of this asymmetry is that exogenous sources of AI-2, but not CAI-1, contribute to satisfying the coincidence detector to repress biofilm formation and promote dispersal. We propose that V. cholerae uses CAI-1 to verify that some of its kin are present before committing to the high-cell-density QS mode, but it is, in fact, the broadly made autoinducer AI-2 that sets the pace of the V. cholerae QS program. This first report of unique roles for the different V. cholerae autoinducers suggests that detection of kin fosters a distinct outcome from detection of nonkin.}, 
location = {Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America. Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.}, }

@Article{Mok2003,
author = {Mok, KC and Wingreen, NS and Bassler, BL}, 
title = {Vibrio harveyi quorum sensing: a coincidence detector for two autoinducers controls gene expression.}, 
journal = {EMBO J}, 
volume = {22}, 
number = {4}, 
pages = {870--881}, 
year = {2003}, 
abstract = {In a process called quorum sensing, bacteria communicate with one another by exchanging chemical signals called autoinducers. In the bioluminescent marine bacterium Vibrio harveyi, two different auto inducers (AI-1 and AI-2) regulate light emission. Detection of and response to the V.harveyi autoinducers are accomplished through two two-component sensory relay systems: AI-1 is detected by the sensor LuxN and AI-2 by LuxPQ. Here we further define the V.harveyi quorum-sensing regulon by identifying 10 new quorum-sensing-controlled target genes. Our examination of signal processing and integration in the V.harveyi quorum-sensing circuit suggests that AI-1 and AI-2 act synergistically, and that the V.harveyi quorum-sensing circuit may function exclusively as a `coincidence detector' that discriminates between conditions in which both autoinducers are present and all other conditions.}, 
location = {Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.}, }

@Article{Auchtung2006,
author = {Auchtung, JM and Lee, CA and Grossman, AD}, 
title = {Modulation of the ComA-dependent quorum response in Bacillus subtilis by multiple Rap proteins and Phr peptides.}, 
journal = {J Bacteriol}, 
volume = {188}, 
number = {14}, 
pages = {5273--5285}, 
year = {2006}, 
abstract = {In Bacillus subtilis, extracellular peptide signaling regulates several biological processes. Secreted Phr signaling peptides are imported into the cell and act intracellularly to antagonize the activity of regulators known as Rap proteins. B. subtilis encodes several Rap proteins and Phr peptides, and the processes regulated by many of these Rap proteins and Phr peptides are unknown. We used DNA microarrays to characterize the roles that several rap-phr signaling modules play in regulating gene expression. We found that rapK-phrK regulates the expression of a number of genes activated by the response regulator ComA. ComA activates expression of genes involved in competence development and the production of several secreted products. Two Phr peptides, PhrC and PhrF, were previously known to stimulate the activity of ComA. We assayed the roles that PhrC, PhrF, and PhrK play in regulating gene expression and found that these three peptides stimulate ComA-dependent gene expression to different levels and are all required for full expression of genes activated by ComA. The involvement of multiple Rap proteins and Phr peptides allows multiple physiological cues to be integrated into a regulatory network that modulates the timing and magnitude of the ComA response.}, 
location = {Department of Biology, Building 68-530, MIT, Cambridge, MA 02139, USA.}, }

@Article{Voichek2020,
author = {Voichek, M and Maaß, S and Kroniger, T and Becher, D and Sorek, R}, 
title = {Peptide-based quorum sensing systems in Paenibacillus polymyxa.}, 
journal = {Life Sci Alliance}, 
volume = {3}, 
number = {10}, 
pages = {e202000847}, 
year = {2020}, 
abstract = {Paenibacillus polymyxa is an agriculturally important plant growth-promoting rhizobacterium. Many Paenibacillus species are known to be engaged in complex bacteria-bacteria and bacteria-host interactions, which in other species were shown to necessitate quorum sensing communication. However, to date, no quorum sensing systems have been described in Paenibacillus Here, we show that the type strain P. polymyxa ATCC 842 encodes at least 16 peptide-based communication systems. Each of these systems is comprised of a pro-peptide that is secreted to the growth medium and processed to generate a mature short peptide. Each peptide has a cognate intracellular receptor of the RRNPP family, and we show that external addition of P. polymyxa communication peptides leads to reprogramming of the transcriptional response. We found that these quorum sensing systems are conserved across hundreds of species belonging to the Paenibacillaceae family, with some species encoding more than 25 different peptide-receptor pairs, representing a record number of quorum sensing systems encoded in a single genome.}, 
location = {Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany. Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany. Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel rotem.sorek@weizmann.ac.il.}, }

@Article{Dekimpe2009,
author = {Dekimpe, V and Déziel, E}, 
title = {Revisiting the quorum-sensing hierarchy in Pseudomonas aeruginosa: the transcriptional regulator RhlR regulates LasR-specific factors.}, 
journal = {Microbiology (Reading)}, 
volume = {155}, 
number = {Pt 3}, 
pages = {712--723}, 
year = {2009}, 
abstract = {Pseudomonas aeruginosa uses the two major quorum-sensing (QS) regulatory systems las and rhl to modulate the expression of many of its virulence factors. The las system is considered to stand at the top of the QS hierarchy. However, some virulence factors such as pyocyanin have been reported to still be produced in lasR mutants under certain conditions. Interestingly, such mutants arise spontaneously under various conditions, including in the airways of cystic fibrosis patients. Using transcriptional lacZ reporters, LC/MS quantification and phenotypic assays, we have investigated the regulation of QS-controlled factors by the las system. Our results show that activity of the rhl system is only delayed in a lasR mutant, thus allowing the expression of multiple virulence determinants such as pyocyanin, rhamnolipids and C(4)-homoserine lactone (HSL) during the late stationary phase. Moreover, at this stage, RhlR is able to overcome the absence of the las system by activating specific LasR-controlled functions, including production of 3-oxo-C(12)-HSL and Pseudomonas quinolone signal (PQS). P. aeruginosa is thus able to circumvent the deficiency of one of its QS systems by allowing the other to take over. This work demonstrates that the QS hierarchy is more complex than the model simply presenting the las system above the rhl system.}, 
location = {INRS-Institut Armand-Frappier, Laval, Québec H7V 1B7, Canada.}, 
keywords = {hierarchy},}

@Article{Eldar2011,
author = {Eldar, A}, 
title = {Social conflict drives the evolutionary divergence of quorum sensing.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {108}, 
number = {33}, 
pages = {13635--13640}, 
year = {2011}, 
abstract = {In microbial  (QS) communication systems, microbes produce and respond to a signaling molecule, enabling a cooperative response at high cell densities. Many species of bacteria show fast, intraspecific, evolutionary divergence of their QS pathway specificity--signaling molecules activate cognate receptors in the same strain but fail to activate, and sometimes inhibit, those of other strains. Despite many molecular studies, it has remained unclear how a signaling molecule and receptor can coevolve, what maintains diversity, and what drives the evolution of cross-inhibition. Here I use mathematical analysis to show that when QS controls the production of extracellular enzymes----diversification can readily evolve. Coevolution is positively selected by cycles of alternating  receptor mutations and  signaling mutations. The maintenance of diversity and the evolution of cross-inhibition between strains are facilitated by facultative cheating between the competing strains. My results suggest a role for complex social strategies in the long-term evolution of QS systems. More generally, my model of QS divergence suggests a form of kin recognition where different kin types coexist in unstructured populations.}, 
location = {Department of Molecular Microbiology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. avigdore@tau.ac.il}, }

@Article{Kostylev2019,
author = {Kostylev, M and Kim, DY and Smalley, NE and Salukhe, I and Greenberg, EP and Dandekar, AA}, 
title = {Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy.}, 
journal = {Proc Natl Acad Sci U S A}, 
volume = {116}, 
number = {14}, 
pages = {7027--7032}, 
year = {2019}, 
abstract = {The bacterial pathogen Pseudomonas aeruginosa activates expression of many virulence genes in a cell density-dependent manner by using an intricate quorum-sensing (QS) network. QS in P. aeruginosa involves two acyl-homoserine-lactone circuits, LasI-LasR and RhlI-RhlR. LasI-LasR is required to activate many genes including those coding for RhlI-RhlR. P. aeruginosa causes chronic infections in the lungs of people with cystic fibrosis (CF). In these infections, LasR mutants are common, but rhlR-rhlI expression has escaped LasR regulation in many CF isolates. To better understand the evolutionary trajectory of P. aeruginosa QS in chronic infections, we grew LasR mutants of the well-studied P. aeruginosa strain, PAO1, in conditions that recapitulate an environment where QS signal synthesis by other bacteria might still occur. When QS is required for growth, addition of the RhlI product butyryl-homoserine lactone (C4-HSL), or bacteria that produce C4-HSL, to LasR mutants results in the rapid emergence of a population with a LasR-independent RhlI-RhlR QS system. These evolved populations exhibit subsequent growth without added C4-HSL. The variants that emerge have mutations in mexT, which codes for a transcription factor that controls expression of multiple genes. LasR-MexT mutants have a competitive advantage over both the parent LasR mutant and a LasR-MexT-RhlR mutant. Our findings suggest a plausible evolutionary trajectory for QS in P. aeruginosa CF infections where LasR mutants arise during infection, but because these mutants are surrounded by C4-HSL-producing P. aeruginosa, variants rewired to have a LasR-independent RhlIR system quickly emerge.}, 
location = {Department of Microbiology, University of Washington, Seattle, WA 98195. Department of Medicine, University of Washington, Seattle, WA 98195. Department of Microbiology, University of Washington, Seattle, WA 98195. Department of Microbiology, University of Washington, Seattle, WA 98195; epgreen@uw.edu dandekar@uw.edu. Department of Microbiology, University of Washington, Seattle, WA 98195; epgreen@uw.edu dandekar@uw.edu. Department of Medicine, University of Washington, Seattle, WA 98195.}, }

@Article{Keegan2023,
author = {Keegan, Nicholas R and Colón Torres, Nathalie J and Stringer, Anne M and Prager, Lia I and Brockley, Matthew W and McManaman, Charity L and Wade, Joseph T and Paczkowski, Jon E}, 
title = {Promoter selectivity of the RhlR quorum-sensing transcription factor receptor in Pseudomonas aeruginosa is coordinated by distinct and overlapping dependencies on C4-homoserine lactone and PqsE.}, 
journal = {PLoS Genet}, 
volume = {19}, 
number = {12}, 
pages = {e1010900}, 
year = {2023}, 
abstract = {Quorum sensing is a mechanism of bacterial cell-cell communication that relies on the production and detection of small molecule autoinducers, which facilitate the synchronous expression of genes involved in group behaviors, such as virulence factor production and biofilm formation. The Pseudomonas aeruginosa quorum sensing network consists of multiple interconnected transcriptional regulators, with the transcription factor, RhlR, acting as one of the main drivers of quorum sensing behaviors. RhlR is a LuxR-type transcription factor that regulates its target genes when bound to its cognate autoinducer, C4-homoserine lactone, which is synthesized by RhlI. RhlR function is also regulated by the metallo-β-hydrolase enzyme, PqsE. We recently showed that PqsE binds RhlR to alter its affinity for promoter DNA, a new mechanism of quorum-sensing receptor activation. Here, we perform ChIP-seq analyses of RhlR to map the binding of RhlR across the P. aeruginosa genome, and to determine the impact of C4-homoserine lactone and PqsE on RhlR binding to different sites across the P. aeruginosa genome. We identify 40 RhlR binding sites, all but three of which are associated with genes known to be regulated by RhlR. C4-homoserine lactone is required for maximal binding of RhlR to many of its DNA sites. Moreover, C4-homoserine lactone is required for maximal RhlR-dependent transcription activation from all sites, regardless of whether it impacts RhlR binding to DNA. PqsE is required for maximal binding of RhlR to many DNA sites, with similar effects on RhlR-dependent transcription activation from those sites. However, the effects of PqsE on RhlR specificity are distinct from those of C4-homoserine lactone, and PqsE is sufficient for RhlR binding to some DNA sites in the absence of C4-homoserine lactone. Together, C4-homoserine lactone and PqsE are required for RhlR binding at the large majority of its DNA sites. Thus, our work reveals three distinct modes of activation by RhlR: i) when RhlR is unbound by autoinducer but bound by PqsE, ii) when RhlR is bound by autoinducer but not bound by PqsE, and iii) when RhlR is bound by both autoinducer and PqsE, establishing a stepwise mechanism for the progression of the RhlR-RhlI-PqsE quorum sensing pathway in P. aeruginosa.}, 
location = {Department of Biomedical Sciences, University at Albany, School of Public Health, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America. Department of Biological Sciences, University at Albany, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America. Department of Biological Sciences, University at Albany, Albany, New York, United States of America. Department of Biomedical Sciences, University at Albany, School of Public Health, Albany, New York, United States of America. Department of Biomedical Sciences, University at Albany, School of Public Health, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America. Department of Biomedical Sciences, University at Albany, School of Public Health, Albany, New York, United States of America. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.}, }