Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa.
TL;DR: It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect, and this review highlights the possible manifestations of PCN exposure.
Abstract: Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species. The limitations of studies are, to date, focused on the localized effect of the release of pyocyanin (PCN). It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect. This review highlights the possible manifestations of PCN exposure; however, most studies to date are in vitro. Further high quality in vivo studies are needed to fully assess the physiological manifestations of PCN exposure on the various body systems.
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TL;DR: The central regulatory role of quorum sensing and signaling systems by nucleotide-based second messengers resulting in different lifestyles of P. aeruginosa is reviewed and various regulatory proteins will be discussed which form a plethora of controlling systems acting at transcriptional level for timely expression of genes enabling rapid responses to external stimuli and unfavorable conditions.
Abstract: Pseudomonas aeruginosa is an opportunistic pathogen affecting immunocompromised patients. It is known as the leading cause of morbidity and mortality in cystic fibrosis (CF) patients and as one of the leading causes of nosocomial infections. Due to a range of mechanisms for adaptation, survival and resistance to multiple classes of antibiotics, infections by P. aeruginosa strains can be life-threatening and it is emerging worldwide as public health threat. This review highlights the diversity of mechanisms by which P. aeruginosa promotes its survival and persistence in various environments and particularly at different stages of pathogenesis. We will review the importance and complexity of regulatory networks and genotypic-phenotypic variations known as adaptive radiation by which P. aeruginosa adjusts physiological processes for adaptation and survival in response to environmental cues and stresses. Accordingly, we will review the central regulatory role of quorum sensing and signaling systems by nucleotide-based second messengers resulting in different lifestyles of P. aeruginosa. Furthermore, various regulatory proteins will be discussed which form a plethora of controlling systems acting at transcriptional level for timely expression of genes enabling rapid responses to external stimuli and unfavorable conditions. Antibiotic resistance is a natural trait for P. aeruginosa and multiple mechanisms underlying different forms of antibiotic resistance will be discussed here. The importance of each mechanism in conferring resistance to various antipseudomonal antibiotics and their prevalence in clinical strains will be described. The underlying principles for acquiring resistance leading pan-drug resistant strains will be summarized. A future outlook emphasizes the need for collaborative international multidisciplinary efforts to translate current knowledge into strategies to prevent and treat P. aeruginosa infections while reducing the rate of antibiotic resistance and avoiding the spreading of resistant strains.
849 citations
TL;DR: It is argued that the way that bacteria live - often in dense and genetically diverse communities - is likely to be key to their aggression as it encourages them to dig in and fight alongside their clonemates.
265 citations
Cites background from "Cellular Effects of Pyocyanin, a Se..."
...There is experimental evidence that pyocyanin can serve in bacterial warfare [43], cell–cell signalling among clonemates [103], pathogenesis [104], and metabolism (as an alternative electron acceptor for respiration) [105]....
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TL;DR: A review of the main virulence factors of Pseudomonas aeruginosa and the adaptations it undergoes to persist in hostile environments such as the CF respiratory tract is presented in this paper.
Abstract: Pseudomonas aeruginosa is a dominant pathogen in people with cystic fibrosis (CF) contributing to morbidity and mortality. Its tremendous ability to adapt greatly facilitates its capacity to cause chronic infections. The adaptability and flexibility of the pathogen are afforded by the extensive number of virulence factors it has at its disposal, providing P. aeruginosa with the facility to tailor its response against the different stressors in the environment. A deep understanding of these virulence mechanisms is crucial for the design of therapeutic strategies and vaccines against this multi-resistant pathogen. Therefore, this review describes the main virulence factors of P. aeruginosa and the adaptations it undergoes to persist in hostile environments such as the CF respiratory tract. The very large P. aeruginosa genome (5 to 7 MB) contributes considerably to its adaptive capacity; consequently, genomic studies have provided significant insights into elucidating P. aeruginosa evolution and its interactions with the host throughout the course of infection.
147 citations
TL;DR: The evaluation of the potential use of ITCs to replace or support the common antibiotics and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health is evaluated.
Abstract: The use of plant-derived products as antimicrobial agents has been investigated in depth. Isothiocyanates (ITCs) are bioactive products resulting from enzymatic hydrolysis of glucosinolates (GLs), the most abundant secondary metabolites in the botanical order Brassicales. Although the antimicrobial activity of ITCs against foodborne and plant pathogens has been well documented, little is known about their antimicrobial properties against human pathogens. This review collects studies that focus on this topic. Particular focus will be put on ITCs’ antimicrobial properties and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health. Our purpose was the evaluation of the potential use of ITCs to replace or support the common antibiotics. Even though ITCs appear to be effective against the most important human pathogens, including bacteria with resistant phenotypes, the majority of the studies did not show comparable results and thus it is very difficult to compare the antimicrobial activity of the different ITCs. For this reason, a standard method should be used and further studies are needed.
120 citations
Cites background from "Cellular Effects of Pyocyanin, a Se..."
...aeruginosa regulates not only biofilm production, but also the release of important virulence factor such as pyocyanin that affects the central nervous system, the urolological and the vascular system inducing inflammatory effect [96] and rhamnolipid involved in the P....
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TL;DR: The potential role of P. aeruginosa virulence factors including phenazines, quorum sensing, biofilm formation and siderophores along with host factors such as Tamm-Horsfall protein, osmotic stress and iron specifically on establishment of successful infection in the urinary niche is explored.
Abstract: Pseudomonas aeruginosa can cause complicated urinary tract infections, particularly in people with catheters, which can lead to pyelonephritis. Whilst some subgroups appear more susceptible to infection, such as the elderly and women, the contribution of other host factors and bacterial virulence factors to successful infection remains relatively understudied. In this review, we explore the potential role of P. aeruginosa virulence factors including phenazines, quorum sensing, biofilm formation and siderophores along with host factors such as Tamm-Horsfall protein, osmotic stress and iron specifically on establishment of successful infection in the urinary niche. P. aeruginosa urinary tract infections are highly antibiotic resistant and require costly and intensive treatment. By understanding the infection dynamics of this organism within this specific niche, we may be able to identify novel therapeutic strategies to enhance the use of existing antibiotics.
106 citations
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TL;DR: This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis and potential future therapies.
Abstract: This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.
1,595 citations
"Cellular Effects of Pyocyanin, a Se..." refers background in this paper
...High molecular weight DNA increases the viscosity of the mucous and ultimately contributes to decreased mucociliary clearance [67]....
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TL;DR: As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases.
Abstract: While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host.
1,584 citations
"Cellular Effects of Pyocyanin, a Se..." refers background in this paper
...Neutrophils are additionally responsible for the release of large amounts of elastase and other proteases [56,63], as well as various oxidants and enzymes [64], all contributing factors to the progressive lung destruction experienced by CF and bronchiectasis patients [63,65]....
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TL;DR: Determination of spontaneous mutation rates in 128 P. aeruginosa isolates from 30 CF patients revealed that 36% of the patients were colonized by a hypermutable (mutator) strain that persisted for years in most patients, revealing a link between high mutations rates in vivo and the evolution of antibiotic resistance.
Abstract: The lungs of cystic fibrosis (CF) patients are chronically infected for years by one or a few lineages of Pseudomonas aeruginosa These bacterial populations adapt to the highly compartmentalized and anatomically deteriorating lung environment of CF patients, as well as to the challenges of the immune defenses and antibiotic therapy These selective conditions are precisely those that recent theoretical studies predict for the evolution of mechanisms that augment the rate of variation Determination of spontaneous mutation rates in 128 P aeruginosa isolates from 30 CF patients revealed that 36% of the patients were colonized by a hypermutable (mutator) strain that persisted for years in most patients Mutator strains were not found in 75 non-CF patients acutely infected with P aeruginosa This investigation also reveals a link between high mutation rates in vivo and the evolution of antibiotic resistance
1,472 citations
"Cellular Effects of Pyocyanin, a Se..." refers background in this paper
...One such compound is pyocyanin (PCN) [8] which has been widely studied to date and is emerging as a virulence factor of interest given the antimicrobial resistant, chronic nature of pseudomonal infections [9]....
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TL;DR: The RANTES protein3 of the C-C class causes the selective migration of human blood monocytes and of T lymphocytes expressing the cell surface antigens CD4 and UCHL1, and may provide insight into the workings of T cell memory.
Abstract: An important process in the immune response is the migration of different populations of lymphocytes at the proper time to sites of antigenic challenge. Although several chemoattractants are known for broad classes of lymphocytes, such as T and B cells, the process by which lymphocytes of specific subsets, such as helper, cytotoxic or memory T cells, migrate to the appropriate sites remains obscure. Interleukin-8 is a chemoattractant for T cells and neutrophils and is a member of a superfamily of soluble molecules related by a conserved motif containing four cysteine residues. IL-8 and related molecules, including platelet factor 4, constitute the C-X-C class of the superfamily and a group of cytokines produced by haematopoietic cells constitute the RANTES/sis or C-C class. The roles of most of these molecules are not well known, although murine MIP-1 alpha of the C-C branch is a specific inhibitor of haematopoietic stem cell proliferation and some members of the C-X-C branch are neutrophil-targeted inflammatory agents. Here we report that the RANTES protein of the C-C class causes the selective migration of human blood monocytes and of T lymphocytes expressing the cell surface antigens CD4 and UCHL1. CD4+/UCHL1+T cells are thought to be prestimulated or primed helper T cells involved in memory T cell function. The preferential attraction of T-cell subsets by specific cytokines could in part explain how lymphocytes are targeted, and may provide insight into the workings of T cell memory.
1,390 citations
"Cellular Effects of Pyocyanin, a Se..." refers background in this paper
...PCN has been shown to exert various other effects on inflammation including its ability to decrease Regulated upon Activation, Normal T Expressed and Secreted (RANTES) [52], an important chemokine involved in the chemoattraction of macrophages and CD4+ memory T-cells [69]....
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...PCN has been shown to inhibit the release of interleukin (IL)-2 [37,52,53] and decreases the expression of IL-2 receptors on T-cells [34,53]....
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TL;DR: Pseudomonas aeruginosa is an ubiquitous pathogen capable of infecting virtually all tissues as discussed by the authors, and a large variety of virulence factors contribute to its importance in burn wounds, lung infection and eye infection.
1,342 citations