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Pseudomonas aeruginosa is an opportunistic human pathogen that infects immunocompromised individuals such as those suffering from burns or the genetic disorder cystic fibrosis. This organism utilizes a cell-cell communication mechanism known as quorum sensing (QS) to coordinate virulence gene expression and biofilm formation. It has three interconnected QS systems, namely las, rhl and pqs. Each system is comprised of autoinducer synthesis genes, lasI, rhlI, and pqsABCDH, and the cognate regulatory genes, lasR, rhlR, and pqsR, respectively. Here, we primarily focused on understanding the regulatory mechanisms of QS, which we investigated at two levels. First, we sought to identify additional activators that regulate QS at the level of the las and rhl systems, and second, we investigated the regulation of downstream genes, particularly biofilm exopolysaccharide genes, by QS. For the first approach, we employed a mutagenesis screen to identify global QS activators. We screened a non-redundant transposon library for mutants deficient in QS-dependent phenotypes. We identified a novel regulator, GidA, a glucose-inhibited cell division protein, that selectively controls QS gene expression posttranscriptionally via RhlR-dependent and -independent pathways. For the second part, we established a regulatory link between QS and Pel exopolysaccharide. We showed that the las system represses Pel and modulates colony biofilm structure through the pqs pathway. LasR mediated colony rugosity via 4-hydroxy-2-alkylquinolines in a PqsR-independent manner, ascribing a novel function to this class of signaling molecules in P. aeruginosa. Taken together, our study highlights the complexity of QS, which involves integration of various regulatory pathways to control downstream processes in response to different environmental conditions.
Pseudomonas comprises three volumes covering the biology of pseudomonads in a wide context, including the niches they inhabit, the taxonomic relations among members of this group, the molecular biology of gene expression in different niches and under different environmental conditions, the analysis of virulence traits in plants, animals and human pathogens as well as the determinants that make some strains useful for biotechnological applications and promotion of plant growth. There has been growing interest in pseudomonads and a particular urge to understand the biology underlying the complex metabolism of these ubiquitous microbes. These bacteria are capable of colonizing a wide range of niches, including the soil, the plant rhizosphere and phylosphere, and animal tissues; more recently they have attracted attention because of their capacity to form biofilms, a characteristic with potentially important medical and environmental implications. The three volumes cover the following topics: - Taxonomy, - Genomics, - Life styles, - Cell Architecture, - Virulence, - Regulation, - Macromolecules, - Alternative Respiratory Substrates, - Catabolism and Biotransformations. Pseudomonas will be of use to all researchers working on these bacteria, particularly those studying microbiology, plant crops, pathogenesis, and chemical engineering. Advanced students in biology, medicine and agronomy will also find these three volumes a valuable reference during their studies.
A comprehensive compendium of scholarly contributions relating to bacterial virulence gene regulation. • Provides insights into global control and the switch between distinct infectious states (e.g., acute vs. chronic). • Considers key issues about the mechanisms of gene regulation relating to: surface factors, exported toxins and export mechanisms. • Reflects on how the regulation of intracellular lifestyles and the response to stress can ultimately have an impact on the outcome of an infection. • Highlights and examines some emerging regulatory mechanisms of special significance. • Serves as an ideal compendium of valuable topics for students, researchers and faculty with interests in how the mechanisms of gene regulation ultimately affect the outcome of an array of bacterial infectious diseases.
Cell-to-cell communication by chemical signals, termed quorum sensing (QS), is a common regulatory scheme in the microbial world. Pseudomonas aeruginosa, an opportunistic pathogen of burn wounds and cystic fibrosis lungs, uses QS to control the expression of hundreds of genes, particularly those necessary for population level benefits such as biofilm formation and secretion of extracellular virulence factors (so-called public goods). P. aeruginosa has two QS systems, las and rhl, that use diffusible acyl-homoserine lactone signals (acyl-HSL). Each system is comprised of a signal synthase (LasI and RhlI) and a cognate receptor transcription factor (LasR and RhlR). Under certain conditions, the las system regulates the rhl system. The circuitry is subject to additional regulation as accumulation of signal is necessary, but not sufficient to activate most QS-controlled genes. From a social evolution perspective, P. aeruginosa QS is considered a cooperative behavior that can be exploited by lasR mutant cheaters that do not contribute public goods. Here, we answer two questions: how social cheating influences the evolution of quorum-sensing inhibitor (QSI) resistance, and what nutritional cues promote QS gene expression. We designed a proof-of-concept experiment to understand how bacterial social interactions affect the evolution of resistance to QSI antivirulence. We cultured QS-deficient mutants with small proportions of QS-proficient wild-type to mimic QSI-sensitive and QSI-resistant cells, respectively. We employed two different carbon sources that are degraded by QS-controlled extracellular, secreted (public) or cell-associated (private) enzymes. We found that QSI-sensitive mimics (QS-deficient cells) behave as social cheaters that delayed population growth and prevented enrichment of QSI-resistant mimics (QS-proficient cells) only when nutrient acquisition was public, suggesting that QSI resistance would not spread. To answer the second question, we used minimal medium batch and chemostat cultures to demonstrate that specific macronutrient starvation coupled with growth rate reduction induces expression of secreted factors directly controlled by the las and rhl QS systems. The rhl system was more responsive to starvation and growth rate reduction as the transcriptional regulator RhlR and its cognate acyl-HSL were strongly induced. Our results also showed that a slow growth rate inverted the las-to-rhl acyl-HSL signal ratio, previously considered a distinguishing characteristic between planktonic and biofilm lifestyles. Importantly, expression level depended on the elemental composition of the secreted product and increased only when the limiting nutrient was not also a building block. Such supply-driven regulation is metabolically prudent as it reduces the costs associated with public goods production, which in turn can help limit the metabolic advantage of non-secreting social cheaters. Our results define the physiological basis for the co-regulation of QS-controlled genes by stress responses. They have implications for the evolutionary stability of microbial cooperation as well as for the efficacy of antivirulence drugs and the emergence of resistance to these drugs.
Abstract: The transcriptional regulatory network of the Pseudomonas aeruginosa quorum sensing system is hierarchical and highly complex as it receives multiple inputs and affects global gene expression. Acyl-homoserine lactone signaling is triggered by the activation of two regulatory proteins--LasR and RhIR. In an effort to better understand the structure of this network and how gene expression signals propagate, the transcription factors that are directly activated by LasR and RhIR were first identified. An in vivo binding assay showed that LasR directly activates the transcriptional regulators rhIR, rsaL, vqsR , and a novel target PA4778 , while RhIR activates vqsR expression. The novel LasR/ PA4778 promoter interaction was verified with an in vitro binding assay, and the LasR binding motif was identified through both sequence analysis and site-directed-mutagenesis. The framework of the quorum sensing transcriptional regulatory network was further expanded by studying PA4778 and its target genes. PA4778 is a MerR-type transcriptional regulator, and its role in copper resistance is demonstrated. Transcriptional profiling of the PA4778 mutant led to a putative PA4778 binding site, which was verified with an in vitro binding assay. PA4778 directly activates the expression of 11 genes that are grouped into five transcriptional units-- PA3519-15, PA3520, mexPQ-opmE, copZ , and cueA , a virulence factor in a murine model. This work illustrates that the quorum sensing system of Pseudomonas aeruginosa exerts its global effects on gene expression in part by triggering smaller regulatory cascades, and further it is shown that these regulatory cascades may respond to multiple environmental stimuli.
The book illustrates the role of quorum sensing in the food industry, agriculture, veterinary sciences, and medicine. It highlights the importance of quorum sensing in regulating diverse cellular functions in microbes, including virulence, pathogenesis, controlled-gene expression systems, and antibiotic resistance. This book also describes the role of quorum sensing in survival behavior and antibiotic resistance in bacteria. Further, it reviews the major role played by quorum sensing in food spoilage, biofilm formation, and food-related pathogenesis. It also explores the methods for the detection and quantification of quorum sensing signals. It also presents antimicrobial and anti-quorum sensing activities of medicinal plants. Finally, the book elucidates a comprehensive yet representative description of basic and applied aspects of quorum sensing inhibitors. This book serves an ideal guide for researchers to understand the implications of quorum sensing in the food industry, medicine, and agriculture.
Bacteria in various habitats are subject to continuously changing environmental conditions, such as nutrient deprivation, heat and cold stress, UV radiation, oxidative stress, dessication, acid stress, nitrosative stress, cell envelope stress, heavy metal exposure, osmotic stress, and others. In order to survive, they have to respond to these conditions by adapting their physiology through sometimes drastic changes in gene expression. In addition they may adapt by changing their morphology, forming biofilms, fruiting bodies or spores, filaments, Viable But Not Culturable (VBNC) cells or moving away from stress compounds via chemotaxis. Changes in gene expression constitute the main component of the bacterial response to stress and environmental changes, and involve a myriad of different mechanisms, including (alternative) sigma factors, bi- or tri-component regulatory systems, small non-coding RNA’s, chaperones, CHRIS-Cas systems, DNA repair, toxin-antitoxin systems, the stringent response, efflux pumps, alarmones, and modulation of the cell envelope or membranes, to name a few. Many regulatory elements are conserved in different bacteria; however there are endless variations on the theme and novel elements of gene regulation in bacteria inhabiting particular environments are constantly being discovered. Especially in (pathogenic) bacteria colonizing the human body a plethora of bacterial responses to innate stresses such as pH, reactive nitrogen and oxygen species and antibiotic stress are being described. An attempt is made to not only cover model systems but give a broad overview of the stress-responsive regulatory systems in a variety of bacteria, including medically important bacteria, where elucidation of certain aspects of these systems could lead to treatment strategies of the pathogens. Many of the regulatory systems being uncovered are specific, but there is also considerable “cross-talk” between different circuits. Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria is a comprehensive two-volume work bringing together both review and original research articles on key topics in stress and environmental control of gene expression in bacteria. Volume One contains key overview chapters, as well as content on one/two/three component regulatory systems and stress responses, sigma factors and stress responses, small non-coding RNAs and stress responses, toxin-antitoxin systems and stress responses, stringent response to stress, responses to UV irradiation, SOS and double stranded systems repair systems and stress, adaptation to both oxidative and osmotic stress, and desiccation tolerance and drought stress. Volume Two covers heat shock responses, chaperonins and stress, cold shock responses, adaptation to acid stress, nitrosative stress, and envelope stress, as well as iron homeostasis, metal resistance, quorum sensing, chemotaxis and biofilm formation, and viable but not culturable (VBNC) cells. Covering the full breadth of current stress and environmental control of gene expression studies and expanding it towards future advances in the field, these two volumes are a one-stop reference for (non) medical molecular geneticists interested in gene regulation under stress.
Microbial relationships with all life forms can be as free living, symbiotic or pathogenic. Human beings harbor 10 times more microbial cells than their own. Bacteria are found on the skin surface, in the gut and other body parts. Bacteria causing diseases are the most worrisome. Most of the infectious diseases are caused by bacterial pathogens with an ability to form biofilm. Bacteria within the biofilm are up to 1000 times more resistant to antibiotics. This has taken a more serious turn with the evolution of multiple drug resistant bacteria. Health Departments are making efforts to reduce high mortality and morbidity in man caused by them. Bacterial Quorum sensing (QS), a cell density dependent phenomenon is responsible for a wide range of expressions such as pathogenesis, biofilm formation, competence, sporulation, nitrogen fixation, etc. Majority of these organisms that are important for medical, agriculture, aquaculture, water treatment and remediation, archaeological departments are: Aeromonas, Acinetobacter, Bacillus, Clostridia, Enterococcus, Pseudomonas, Vibrio and Yersinia spp. Biosensors and models have been developed to detect QS systems. Strategies for inhibiting QS system through natural and synthetic compounds have been presented here. The biotechnological applications of QS inhibitors (QSIs) in diverse areas have also been dealt with. Although QSIs do not affect growth and are less likely to impose selective pressure on bacteria, however, a few reports have raised doubts on the fate of QSIs. This book addresses a few questions. Will bacteria develop mechanisms to evade QSIs? Are we watching yet another defeat at the hands of bacteria? Or will we be acting intelligently and survive the onslaughts of this Never Ending battle?