A mathematical model of quorum sensing in a growing bacterial biofilm

In a process called quorum sensing, bacteria monitor their population density via extracellular signaling molecules and modulate gene expression accordingly. This paper describes a one-dimensional model of a growing Pseudomonas aeruginosa biofilm. Quorum sensing has been included in the model by the addition of equations describing the production, degradation, and diffusion of acyl-homoserine lactones in the biofilm. In order for quorum sensing to initiate near the substratum, in accordance with experimental observations, model results suggest that cells in oxygen-deficient regions of the biofilm must still be synthesizing the signal compound. This result highlights the importance of careful study of the relationship between metabolic activity of the bacterium and signal synthesis. Received 11 March 2002/ Accepted in revised form 01 August 2002     

The Influence of Fluid Flow on Modeling Quorum Sensing in Bacterial Biofilms

In this paper, we study quorum sensing in Pseudomonas aeruginosa biofilms. Quorum sensing is a process where bacteria monitor their population density through the release of extra-cellular signalling molecules. The presence of these molecules affects gene modulation leading to changes in behaviour such as the release of virulence factors. Here, we use numerical methods to approximate a 2-D model of quorum sensing. It is observed that the shape of the biofilm can have a profound effect on the onset of quorum sensing. This has serious repercussions for experimental observations since biofilms of the same biomass but different shapes can produce quite different results.     

The small regulatory RNA molecule MicA is involved in <Emphasis Type="Italic">Salmonella enterica</Emphasis> serovar Typhimurium biofilm formation

Background  

LuxS is the synthase enzyme of the quorum sensing signal AI-2. In Salmonella Typhimurium, it was previously shown that a luxS deletion mutant is impaired in biofilm formation. However, this phenotype could not be complemented by extracellular addition of quorum sensing signal molecules.     

Modelling antibiotic- and anti-quorum sensing treatment of a spatially-structured Pseudomonas aeruginosa population

The bacterial cell to cell signalling system known as quorum sensing (QS) is essential for the regulation of virulence in many pathogens and offers a specific biochemical target for novel antibacterial therapies. Expanding on earlier work, in which consideration was given to the primary QS system (lasR system) in a homogeneous population of the common human pathogen Pseudomonas aeruginosa, we build a simple spatial model of an early-stage P. aeruginosa biofilm subject to treatment with topically applied anti-QS drugs (of two specific kinds) and conventional antibiotics. In the case of a slowly growing biofilm we show that both kinds of anti-quorum sensing drug are effective in reducing the level of the relevant signal molecule (3-oxo-C12-homoserine lactone; henceforth AHL), in each case obtaining an explicit bound on the steady-state AHL profile in terms of a prescribed surface drug concentration. Using numerical methods, we are also able to reproduce the hysteretic phenomena exhibited by the homogeneous model, in particular showing that for each kind of anti-QS drug there is a parameter regime in which a catastrophic collapse occurs in the steady-state AHL concentration as the surface drug concentration passes some critical value; an alternative way of interpreting this result is to say that, for a prescribed surface drug concentration, there is a critical biofilm depth such that treatment is successful until this depth is reached, but fails thereafter. In the thick-biofilm limit we show that the critical concentration of each drug increases exponentially with the biofilm thickness (or, conversely, that the critical depth increases logarithmically with surface drug concentration); this is dramatically different to the behaviour observed in the corresponding homogeneous model, where the critical concentrations grow linearly with bacterial carrying capacity, and thus highlights the relative difficulty of treating a large, spatially-structured population with diffusing antibacterials.     

废水处理中群体感应调控行为研究进展

群体感应是微生物在繁殖过程中分泌一些特定的信号分子,当信号分子浓度达到一定阈值后,可以调控某些基因表达,从而实现信息交流的现象.群体感应调控着生物膜形成、公共物质合成、基因水平转移等一系列社会性行为,广泛存在于各类微生物信息交流中.活性污泥、生物膜和颗粒污泥等生物聚集体广泛存在群体感应现象,了解和认识群体感应与微生物之间的调控行为,对于废水处理具有重要意义.本文综述了感应信号分子的分类、群体感应调控机制,群体感应在活性污泥、生物膜、好氧颗粒污泥和厌氧颗粒污泥等废水处理中的调控行为的研究进展,并对废水处理中群体感应的研究进行了展望,以期为深入理解废水处理中群体感应调控行为提供参考.     

粘质沙雷氏菌AS-1中SpnR功能及卤化呋喃对其群体感应的抑制

通过分泌和感知一系列信号分子,细菌能够根据自身菌体密度的变化调控基因的表达,从而控制一系列重要的表现型,包括毒力因子的产生,生物膜的形成以及菌体发光等.这种广泛存在的信号机制被称为群体感应.在沙雷氏菌种中已经发现了多套群体感应机制.粘质沙雷氏菌AS-1从土壤中分离,其中含有LuxI/LuxR的同类蛋白,被称为SpnI/SpnR.粘质沙雷氏菌AS-1合成AHLs分子N-hexanoy1-L-homoserinelactone(C6-HSL)和N-(3.oxohexanoyl)-L-homoserine lactone(3-oxo-C6-HSL)作为其信号分子,通过群体感应感知菌体密度来控制基因的表达.通过基因替代的方法制得了spnR基因破坏的变异株,命名为粘质沙雷氏菌AS-1R.对粘质沙雷氏菌AS-1R的研究表明SpnR蛋白消极的调控沙雷氏菌红色色素的产生,运动性以及生物膜的形成等一系列由群体感应控制的性状:另一方面,作为一种天然的群体感应抑制剂,卤化呋喃能够有效的抑制粘质沙雷氏菌AS-1的群体感应,但并不干扰AHL-SpnR的相互作用.为运用粘质沙雷氏菌群体感应调节抑制其致病性提供了方法和依据,同时也为卤化呋喃对群体感应抑制机理的研究提供了新的思路.     

群体感应在生物强化功能菌定殖及降解能力增强中的作用研究进展

由于难降解有机污染物和外界环境对水处理系统的冲击干扰,污水水质常出现不达标现象。引入外源含有相关功能基因并且具有基因水平转移能力的工程菌株进行生物强化处理是提高污水处理效能的有效措施。污水处理系统中存在能够分泌信号分子的菌体,菌间具有群体感应现象,当种群密度达到感应阈值时,菌体会通过释放信号分子来触发一些群体行为,从而激活相关基因的表达(如生物膜形成、生物发光、抗生素合成和毒力因子表达等)。早期的群体感应技术研究主要集中在信号传递学、微生物社会行为学和医学微生物领域,近年来,在水处理领域也开始有相继报道,研究表明群体感应在污水生物处理中发挥重要作用,并且影响生物强化菌株的定殖和污染物降解,因此群体感应行为调控是生物强化技术成效显著与否的关键因素。本文综述了群体感应及信号分子的作用机制、信号分子释放及存在的影响因素以及群体感应对菌株定殖、微生物群落结构和污染物去除的影响,并对从群体感应角度出发研究生物强化过程进行了展望,旨在为生物强化技术的有效实施及提升污水处理效能提供一种新思路,为深入理解生物强化过程中群体感应调控行为提供理论参考。     

Quorum sensing and swarming migration in bacteria

Bacterial cells can produce and sense signal molecules, allowing the whole population to initiate a concerted action once a critical concentration (corresponding to a particular population density) of the signal has been reached, a phenomenon known as quorum sensing. One of the possible quorum sensing-regulated phenotypes is swarming, a flagella-driven movement of differentiated swarmer cells (hyperflagellated, elongated, multinucleated) by which bacteria can spread as a biofilm over a surface. The glycolipid or lipopeptide biosurfactants thereby produced function as wetting agent by reducing the surface tension. Quorum sensing systems are almost always integrated into other regulatory circuits. This effectively expands the range of environmental signals that influence target gene expression beyond population density. In this review, we first discuss the regulation of AHL-mediated surface migration and the involvement of other low-molecular-mass signal molecules (such as the furanosyl borate diester AI-2) in biosurfactant production of different bacteria. In addition, population density-dependent regulation of swarmer cell differentiation is reviewed. Also, several examples of interspecies signalling are reported. Different signal molecules either produced by bacteria (such as other AHLs and diketopiperazines) or excreted by plants (such as furanones, plant signal mimics) might influence the quorum sensing-regulated swarming behaviour in bacteria different from the producer. On the other hand, specific bacteria can reduce the local available concentration of signal molecules produced by others. In the last part, the role and regulation of a surface-associated movement in biofilm formation is discussed. Here we also describe how quorum sensing may disperse existing biofilms and control the interaction between bacteria and higher organisms (such as the Rhizobium-bean symbiosis).     

Information transmission in microbial and fungal communication: from classical to quantum

Microbes have their own communication systems. Secretion and reception of chemical signaling molecules and ion-channels mediated electrical signaling mechanism are yet observed two special ways of information transmission in microbial community. In this article, we address the aspects of various crucial machineries which set the backbone of microbial cell-to-cell communication process such as quorum sensing mechanism (bacterial and fungal), quorum sensing regulated biofilm formation, gene expression, virulence, swarming, quorum quenching, role of noise in quorum sensing, mathematical models (therapy model, evolutionary model, molecular mechanism model and many more), synthetic bacterial communication, bacterial ion-channels, bacterial nanowires and electrical communication. In particular, we highlight bacterial collective behavior with classical and quantum mechanical approaches (including quantum information). Moreover, we shed a new light to introduce the concept of quantum synthetic biology and possible cellular quantum Turing test.     

Detection of quorum sensing signal molecules and identification of an autoinducer synthase gene among biofilm forming clinical isolates of Acinetobacter spp

Background

Quorum sensing is a term that describes an environmental sensing system that allows bacteria to monitor their own population density which contributes significantly to the size and development of the biofilm. Many gram negative bacteria use N-acyl-homoserine lactones as quorum sensing signal molecules. In this study, we sought to find out if the biofilm formation among clinical isolates of Acinetobacter spp. is under the control of autoinducing quorum sensing molecules.

Methodology/Principal Findings

Biofilm formation among clinical isolates of Acinetobacter spp. was assessed and the production of signal molecules were detected with Chromobacterium violaceum CV026 biosensor system. Characterisation of autoinducers was carried out by mass spectrometric analysis. We have also reported the identification of an autoinducer synthase gene, abaΙ among the isolates that produce quorum sensing signal molecules and have reported that the mutation in the abaI gene influences their biofilm forming capabilities. Using a microtitre-plate assay it was shown that 60% of the 50 Acinetobacter spp. isolates significantly formed biofilms. Further detection with the biosensor strain showed that some of these isolates produced long chain signal molecules. Mass spectrometric analysis revealed that five of these isolates produced N-decanoyl homoserine lactone and two isolates produced acyl-homoserine lactone with a chain length equal to C₁₂. The abaΙ gene was identified and a tetracycline mutant of the abaΙ gene was created and the inhibition in biofilm formation in the mutant was shown.

Conclusions/Significance

These data are of great significance as the signal molecules aid in biofilm formation which in turn confer various properties of pathogenicity to the clinical isolates including drug resistance. The use of quorum sensing signal blockers to attenuate bacterial pathogenicity is therefore highly attractive, particularly with respect to the emergence of multi antibiotic resistant bacteria.     

群体感应与微生物耐药性

微生物耐药性已成为全球关注的严重问题,其演化机制和调控机理也已成为研究热点。近年来的研究发现,一些微生物耐药性机制受到群体感应系统的调控。群体感应是一种在微生物界广泛存在并与菌体密度关联的细胞-细胞间的通讯系统。高密度的菌落群体能够产生足够数量的小分子信号,激活下游包括致病毒力和耐药性机制在内的多种细胞进程,耐受抗生素并且危害寄主。本文结合国内外最新的研究进展,对微生物群体感应系统的研究现状进行了概括性介绍,重点阐述了群体感应系统对微生物耐药性机制的调控作用,如微生物生物被膜形成和药物外排泵调控等方面的作用,并探讨了利用群体淬灭控制微生物耐药性的新策略。     

Quorum sensing: How bacteria can coordinate activity and synchronize their response to external signals?

Quorum sensing is used by a large variety of bacteria to regulate gene expression in a cell-density-dependent manner. Bacteria can synchronize population behavior using small molecules called autoinducers that are produced by cognate synthases and recognized by specific receptors. Quorum sensing plays critical roles in regulating diverse cellular functions in bacteria, including bioluminescence, virulence gene expression, biofilm formation, and antibiotic resistance. The best-studied autoinducers are acyl homoserine lactone (AHL) molecules, which are the primary quorum sensing signals used by Gram-negative bacteria. In this review we focus on the AHL-dependent quorum sensing system and highlight recent progress on structural and mechanistic studies of AHL synthases and the corresponding receptors. Crystal structures of LuxI-type AHL synthases provide insights into acyl-substrate specificity, but the current knowledge is still greatly limited. Structural studies of AHL receptors have facilitated a more thorough understanding of signal perception and established the molecular framework for the development of quorum sensing inhibitors.     

青岛近海沉积物生物被膜中密度感应及密度感应淬灭细菌多样性

【背景】细菌密度感应(Quorum sensing,QS)是指细菌利用分泌的信号分子进行相互交流的现象,而密度感应淬灭(Quorumquenching,QQ)是指通过干扰信号分子的产生、释放、积累或应答从而阻抑密度感应通路。【目的】探究青岛近海沉积物生物被膜中密度感应和密度感应淬灭细菌的多样性。【方法】采用海水培养基2216E从青岛近海沉积物生物被膜中分离获取可培养细菌,采用平板交互划线和高通量筛选的方法分别筛选具有密度感应和密度感应淬灭的菌株。【结果】共分离获得83株共54种具有密度感应和密度感应淬灭的细菌,分属于四大细菌门类:变形菌门、拟杆菌门、厚壁菌门和放线菌门。其中,38株(45.8%)可以产生酰基高丝氨酸内酯(Acyl-homoserine lactone,AHL)类信号分子,它们分属于变形菌门(37株,15种)和拟杆菌门(1株,1种),优势属为弧菌属和鲁杰氏菌属;能够降解AHL类信号分子的有57株(68.7%),在变形菌门(41株,23种)、拟杆菌门(14株,10种)、厚壁菌门(5株,5种)以及放线菌门(1株,1种)中均有分布。【结论】在青岛近海沉积物生物被膜可培养细菌中,具有密度感应和密度感应淬灭现象的菌株具有很高的丰度和多样性,为后续生态学意义的研究与海洋微生物的开发提供了参考。     

Early development and quorum sensing in bacterial biofilms

 We develop mathematical models to examine the formation, growth and quorum sensing activity of bacterial biofilms. The growth aspects of the model are based on the assumption of a continuum of bacterial cells whose growth generates movement, within the developing biofilm, described by a velocity field. A model proposed in Ward et al. (2001) to describe quorum sensing, a process by which bacteria monitor their own population density by the use of quorum sensing molecules (QSMs), is coupled with the growth model. The resulting system of nonlinear partial differential equations is solved numerically, revealing results which are qualitatively consistent with experimental ones. Analytical solutions derived by assuming uniform initial conditions demonstrate that, for large time, a biofilm grows algebraically with time; criteria for linear growth of the biofilm biomass, consistent with experimental data, are established. The analysis reveals, for a biologically realistic limit, the existence of a bifurcation between non-active and active quorum sensing in the biofilm. The model also predicts that travelling waves of quorum sensing behaviour can occur within a certain time frame; while the travelling wave analysis reveals a range of possible travelling wave speeds, numerical solutions suggest that the minimum wave speed, determined by linearisation, is realised for a wide class of initial conditions. Received: 10 February 2002 / Revised version: 29 October 2002 / Published online: 19 March 2003 Key words or phrases: Bacterial biofilm – Quorum sensing – Mathematical modelling – Numerical solution – Asymptotic analysis – Travelling wave analysis     

Bacterial autoinduction: looking outside the cell for new metabolic engineering targets

Recent evidence has demonstrated that cell-to-cell signaling is a fundamental activity carried out by numerous microorganisms. A number of specialized processes are reported to be regulated by density-dependent signaling molecules including antibiotic production, bioluminescence, biofilm formation, genetic competence, sporulation, swarming motility and virulence. However, a more centralized role for quorum sensing is emerging where quorum signaling pathways overlap with stress and starvation circuits to regulate cellular adaptation to changing environmental conditions. The interplay of these phenomena is especially critical in the expression of recombinant proteins where elicitation of stress responses can dramatically impact cellular productivity.     

The metabolic basis of Candida albicans morphogenesis and quorum sensing

Candida albicans is a polymorphic fungus that has the ability to rapidly switch between yeast and filamentous forms. The morphological transition appears to be a critical virulence factor of this fungus. Recent studies have elucidated the signal transduction pathways and quorum sensing molecules that affect the morphological transition of C. albicans. The metabolic mechanisms that recognize, and respond to, such signaling molecules and promote the morphological changes at a system level, however, remain unknown. Here we review the metabolic basis of C. albicans morphogenesis and we discuss the role of primary metabolic pathways and quorum sensing molecules in the morphogenetic process. We have reconstructed, in silico, the central carbon metabolism and sterol biosynthesis of C. albicans based on its genome sequence, highlighting the metabolic pathways associated with the dimorphic transition and virulence as well as pathways involved in the biosynthesis of important quorum sensing molecules.     

基于Lux型群体感应系统干预的生物被膜调控在污水处理中的研究进展与前景

基于Lux型群体感应系统的生物被膜调控在污水处理中的研究备受关注,群体感应系统的干预包括正向强化和负向削弱两类。群体感应系统的正向强化作用可提高生物膜法污水处理中的挂膜速度,提高污水处理效率,促进活性污泥中胞外聚合物(Extracellular polymeric substance,EPS)和可溶性微生物产物(Soluble microbial products,SMP)的生成,提高生物被膜的产量;群体感应的负向削弱作用可以降解生物被膜形成过程中所需要的信号分子,切断生物被膜形成的基因表达过程,有效抑制MBR膜表面生物被膜的形成,防止膜污染。对信号分子酰基高丝氨酸内酯(N-acyl homoserine lactone,AHLs)的结构和作用机理的进一步研究、群体感应淬灭菌的固定化技术与应用、多种防治膜污染方法的协同效果验证及群体感应干预在更多污水处理领域的应用可行性是该领域要研究的几个重要方向。     

生物聚集体中群体感应作用的研究进展

群体感应是微生物利用信号分子感知环境条件并进行特定基因表达调控.近年来,随着群体感应在微生物信息交流中的作用日益凸显,其在生物聚集体(生物膜和颗粒)形成过程中的作用受到广泛关注.本文综述了自体诱导信号分子AI的分类和相应的群体感应调控方式,以及群体感应信号分子对生物聚集体形成和结构稳定的调控,并对群体感应研究新领域进行了展望.     

Information processing and signal integration in bacterial quorum sensing

Bacteria communicate using secreted chemical signaling molecules called autoinducers in a process known as quorum sensing. The quorum‐sensing network of the marine bacterium Vibrio harveyi uses three autoinducers, each known to encode distinct ecological information. Yet how cells integrate and interpret the information contained within these three autoinducer signals remains a mystery. Here, we develop a new framework for analyzing signal integration on the basis of information theory and use it to analyze quorum sensing in V. harveyi. We quantify how much the cells can learn about individual autoinducers and explain the experimentally observed input–output relation of the V. harveyi quorum‐sensing circuit. Our results suggest that the need to limit interference between input signals places strong constraints on the architecture of bacterial signal‐integration networks, and that bacteria probably have evolved active strategies for minimizing this interference. Here, we analyze two such strategies: manipulation of autoinducer production and feedback on receptor number ratios.     

Active regulation of receptor ratios controls integration of quorum‐sensing signals in Vibrio harveyi

Quorum sensing is a chemical signaling mechanism used by bacteria to communicate and orchestrate group behaviors. Multiple feedback loops exist in the quorum‐sensing circuit of the model bacterium Vibrio harveyi. Using fluorescence microscopy of individual cells, we assayed the activity of the quorum‐sensing circuit, with a focus on defining the functions of the feedback loops. We quantitatively investigated the signaling input–output relation both in cells with all feedback loops present as well as in mutants with specific feedback loops disrupted. We found that one of the feedback loops regulates receptor ratios to control the integration of multiple signals. Together, the feedback loops affect the input–output dynamic range of signal transmission and the noise in the output. We conclude that V. harveyi employs multiple feedback loops to simultaneously control quorum‐sensing signal integration and to ensure signal transmission fidelity.