scholarly journals Roles of Two-Component Systems in Pseudomonas aeruginosa Virulence

2021 ◽  
Vol 22 (22) ◽  
pp. 12152
Author(s):  
Maria Sultan ◽  
Rekha Arya ◽  
Kyeong Kyu Kim
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Opportunistic Pathogen ◽  
Secretion Systems ◽  
Chronic Infections ◽  
Potential Threat ◽  
Wide Range ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

Pseudomonas aeruginosa is an opportunistic pathogen that synthesizes and secretes a wide range of virulence factors. P. aeruginosa poses a potential threat to human health worldwide due to its omnipresent nature, robust host accumulation, high virulence, and significant resistance to multiple antibiotics. The pathogenicity of P. aeruginosa, which is associated with acute and chronic infections, is linked with multiple virulence factors and associated secretion systems, such as the ability to form and utilize a biofilm, pili, flagella, alginate, pyocyanin, proteases, and toxins. Two-component systems (TCSs) of P. aeruginosa perform an essential role in controlling virulence factors in response to internal and external stimuli. Therefore, understanding the mechanism of TCSs to perceive and respond to signals from the environment and control the production of virulence factors during infection is essential to understanding the diseases caused by P. aeruginosa infection and further develop new antibiotics to treat this pathogen. This review discusses the important virulence factors of P. aeruginosa and the understanding of their regulation through TCSs by focusing on biofilm, motility, pyocyanin, and cytotoxins.

scholarly journals Determination of the Two-Component Systems regulatory network reveals core and accessory regulations across Pseudomonas aeruginosa lineages

2021 ◽  
Author(s):  
Julian Trouillon ◽  
Lionel Imbert ◽  
Anne-Marie Villard ◽  
Thierry Vernet ◽  
Ina Attrée ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Binding Sites ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Single Species ◽  
Opportunistic Pathogen ◽  
Physiological Processes ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

Pseudomonas aeruginosa possesses one of the most complex bacterial regulatory networks, which largely contributes to its success as a human opportunistic pathogen. However, most of its transcription factors (TFs) are still uncharacterized and the potential intra-species variability in regulatory networks has been mostly ignored so far. Here, to provide a first global view of the two-component systems (TCSs) regulatory network in P. aeruginosa, we produced and purified all DNA-binding TCS response regulators (RRs) and used DAP-seq to map the genome-wide binding sites of these 55 TFs across the three major P. aeruginosa lineages. The resulting networks encompass about 40% of all genes in each strain and contain numerous new important regulatory interactions across most major physiological processes, including virulence and antibiotic resistance. Strikingly, the comparison between the three representative strains shows that about half of the detected targets are specific to only one or two of the tested strains, revealing a previously unknown large functional diversity of TFs within a single species. Three main mechanisms were found to drive this diversity, including differences in accessory genome content, as exemplified by the strain-specific plasmid in the IHMA87 outlier strain which harbors numerous binding sites of chromosomally-encoded RRs. Additionally, most RRs display potential auto-regulation or RR-RR cross-regulation, bringing to light the vast complexity of this network. Overall, we provide the first complete delineation of the TCS regulatory network in P. aeruginosa that will represent an important resource for future studies on this pathogen.

scholarly journals The two-component system CopRS maintains femtomolar levels of free copper in the periplasm of Pseudomonas aeruginosa using a phosphatase-based mechanism

2020 ◽  
Author(s):  
Lorena Novoa-Aponte ◽  
Fernando C. Soncini ◽  
José M. Argüello
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Phosphatase Activity ◽  
Response Regulator ◽  
Redox Enzymes ◽  
Two Component System ◽  
Component System ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Systems Control

ABSTRACTTwo component systems control periplasmic Cu+ homeostasis in Gram-negative bacteria. In characterized systems such as Escherichia coli CusRS, upon Cu+ binding to the periplasmic sensing domain of CusS, a cytoplasmic phosphotransfer domain phosphorylates the response regulator CusR. This drives the expression of efflux transporters, chaperones, and redox enzymes to ameliorate metal toxic effects. Here, we show that the Pseudomonas aeruginosa two component sensor histidine kinase CopS exhibits a Cu-dependent phosphatase activity that maintains a non-phosphorylated CopR when the periplasmic Cu levels are below its activation threshold. Upon Cu+ binding to the sensor, the phosphatase activity is blocked and the phosphorylated CopR activates transcription of the CopRS regulon. Supporting the model, mutagenesis experiments revealed that the ΔcopS strain showed constitutive high expression of the CopRS regulon, lower intracellular Cu+ levels, and larger Cu tolerance when compared to wild type cells. The invariant phospho-acceptor residue His235 of CopS was not required for the phosphatase activity itself, but necessary for its Cu-dependency. To sense the metal, the periplasmic domain of CopS binds two Cu+ ions at its dimeric interface. Homology modeling of CopS based on CusS structure (four Ag+ binding sites) clearly explains the different binding stoichiometries in both systems. Interestingly, CopS binds Cu+/2+ with 30 × 10−15 M affinities, pointing to the absence of free (hydrated) Cu+/2+ in the periplasm.IMPORTANCECopper is a micronutrient required as cofactor in redox enzymes. When free, copper is toxic, mismetallating proteins, and generating damaging free radicals. Consequently, copper overload is a strategy that eukaryotic cells use to combat pathogens. Bacteria have developed copper sensing transcription factors to control copper homeostasis. The cell envelope is the first compartment that has to cope with copper stress. Dedicated two component systems control the periplasmic response to metal overload. This manuscript shows that the copper sensing two component system present in Pseudomonadales exhibits a signal-dependent phosphatase activity controlling the activation of the response regulator, distinct from previously described periplasmic Cu sensors. Importantly, the data show that the sensor is activated by copper levels compatible with the absence of free copper in the cell periplasm. This emphasizes the diversity of molecular mechanisms that have evolved in various bacteria to manage the copper cellular distribution.

scholarly journals Transcriptomic Analysis of the Sulfate Starvation Response of Pseudomonas aeruginosa

2007 ◽  
Vol 189 (19) ◽  
pp. 6743-6750 ◽  
Author(s):  
Tewes Tralau ◽  
Stéphane Vuilleumier ◽  
Christelle Thibault ◽  
Barry J. Campbell ◽  
C. Anthony Hart ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Stress Proteins ◽  
Large Family ◽  
Opportunistic Pathogen ◽  
Transport Systems ◽  
Sulfur Source ◽  
Secretion Systems ◽  
Starvation Response ◽  
Wide Range

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that causes a number of infections in humans, but is best known for its association with cystic fibrosis. It is able to use a wide range of sulfur compounds as sources of sulfur for growth. Gene expression in response to changes in sulfur supply was studied in P. aeruginosa E601, a cystic fibrosis isolate that displays mucin sulfatase activity, and in P. aeruginosa PAO1. A large family of genes was found to be upregulated by sulfate limitation in both isolates, encoding sulfatases and sulfonatases, transport systems, oxidative stress proteins, and a sulfate-regulated TonB/ExbBD complex. These genes were localized in five distinct islands on the genome and encoded proteins with a significantly reduced content of cysteine and methionine. Growth of P. aeruginosa E601 with mucin as the sulfur source led not only to a sulfate starvation response but also to induction of genes involved with type III secretion systems.

scholarly journals Recent advances in understanding Pseudomonas aeruginosa as a pathogen

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1261 ◽  
Author(s):  
Jens Klockgether ◽  
Burkhard Tümmler
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Population Biology ◽  
Recent Progress ◽  
Human Subjects ◽  
Opportunistic Pathogen ◽  
Mammalian Host ◽  
Secretion Systems ◽  
Chronic Infections ◽  
Type Vi Secretion

The versatile and ubiquitousPseudomonas aeruginosais an opportunistic pathogen causing acute and chronic infections in predisposed human subjects. Here we review recent progress in understandingP. aeruginosapopulation biology and virulence, its cyclic di-GMP-mediated switches of lifestyle, and its interaction with the mammalian host as well as the role of the type III and type VI secretion systems inP. aeruginosainfection.

scholarly journals Mutational Analysis of RetS, an Unusual Sensor Kinase-Response Regulator Hybrid Required for Pseudomonas aeruginosa Virulence

2006 ◽  
Vol 74 (8) ◽  
pp. 4462-4473 ◽  
Author(s):  
Michelle A. Laskowski ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mutational Analysis ◽  
Response Regulator ◽  
Acute Infection ◽  
Opportunistic Pathogen ◽  
Sensor Kinase ◽  
Chronic Infections ◽  
Reciprocal Regulation ◽  
Wide Range

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen capable of causing both acute and chronic infections in a wide range of hosts. Expression of the type III secretion system (T3SS) proteins is correlated with virulence in models of acute infection, while downregulation of the T3SS and upregulation of genes important for biofilm formation are observed during chronic infections. RetS, a hybrid sensor kinase-response regulator protein of P. aeruginosa, plays a key role in the reciprocal regulation of virulence factors required for acute versus chronic infection and is postulated to act in concert with two other sensor kinase-response regulator hybrids, GacS and LadS. This work examines the roles of the putative sensing and signal transduction domains of RetS in induction of the T3SS in vitro and in a murine model of acute pneumonia. We identify distinct signaling roles for the tandem receiver domains of RetS and present evidence suggesting that RetS may serve as a substrate for another sensor kinase. Phenotypes associated with RetS alleles lacking periplasmic and/or transmembrane domains further indicate that the periplasmic domain of RetS may transmit a signal that inhibits RetS activity during acute infections.

scholarly journals The Two-Component Sensor KinB Acts as a Phosphatase To Regulate Pseudomonas aeruginosa Virulence

2012 ◽  
Vol 194 (23) ◽  
pp. 6537-6547 ◽  
Author(s):  
Nikhilesh S. Chand ◽  
Anne E. Clatworthy ◽  
Deborah T. Hung
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Response Regulator ◽  
Opportunistic Pathogen ◽  
Regulatory Control ◽  
Primary Role ◽  
Chronic Infections ◽  
Content Type ◽  
Two Component ◽  
Sense And Respond ◽  
Cognate Response Regulator

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that is capable of causing both acute and chronic infections.P. aeruginosavirulence is subject to sophisticated regulatory control by two-component systems that enable it to sense and respond to environmental stimuli. We recently reported that the two-component sensor KinB regulates virulence in acuteP. aeruginosainfection. Furthermore, it regulates acute-virulence-associated phenotypes such as pyocyanin production, elastase production, and motility in a manner independent of its kinase activity. Here we show that KinB regulates virulence through the global sigma factor AlgU, which plays a key role in repressingP. aeruginosaacute-virulence factors, and through its cognate response regulator AlgB. However, we show that rather than phosphorylating AlgB, KinB's primary role in the regulation of virulence is to act as a phosphatase to dephosphorylate AlgB and alleviate phosphorylated AlgB's repression of acute virulence.

scholarly journals A Large-Scale Whole-Genome Comparison Shows that Experimental Evolution in Response to Antibiotics Predicts Changes in Naturally Evolved Clinical Pseudomonas aeruginosa

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Samuel J. T. Wardell ◽  
Attika Rehman ◽  
Lois W. Martin ◽  
Craig Winstanley ◽  
Wayne M. Patrick ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Experimental Evolution ◽  
Large Scale ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Genome Comparison ◽  
Chronic Infections ◽  
Content Type ◽  
Large Deletions ◽  
Wide Range

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide range of acute and chronic infections. An increasing number of isolates have mutations that make them antibiotic resistant, making treatment difficult. To identify resistance-associated mutations, we experimentally evolved the antibiotic-sensitive strain P. aeruginosa PAO1 to become resistant to three widely used antipseudomonal antibiotics, namely, ciprofloxacin, meropenem, and tobramycin. Mutants could tolerate up to 2,048-fold higher concentrations of antibiotics than strain PAO1. Genome sequences were determined for 13 mutants for each antibiotic. Each mutant had between 2 and 8 mutations. For each antibiotic, at least 8 genes were mutated in multiple mutants, demonstrating the genetic complexity of resistance. For all three antibiotics, mutations arose in genes known to be associated with resistance but also in genes not previously associated with resistance. To determine the clinical relevance of mutations uncovered in this study, we analyzed the corresponding genes in 558 isolates of P. aeruginosa from patients with chronic lung disease and in 172 isolates from the general environment. Many genes identified through experimental evolution had predicted function-altering changes in clinical isolates but not in environmental isolates, showing that mutated genes in experimentally evolved bacteria can predict those that undergo mutation during infection. Additionally, large deletions of up to 479 kb arose in experimentally evolved meropenem-resistant mutants, and large deletions were present in 87 of the clinical isolates. These findings significantly advance understanding of antibiotic resistance in P. aeruginosa and demonstrate the validity of experimental evolution in identifying clinically relevant resistance-associated mutations.

scholarly journals Regulation of Carbon and Nitrogen Utilization by CbrAB and NtrBC Two-Component Systems in Pseudomonas aeruginosa

2007 ◽  
Vol 189 (15) ◽  
pp. 5413-5420 ◽  
Author(s):  
Wei Li ◽  
Chung-Dar Lu
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nitrogen Source ◽  
Tca Cycle ◽  
Nitrogen Utilization ◽  
Model Systems ◽  
Carbon And Nitrogen ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Tca Cycle Intermediates

ABSTRACT The global effect of the CbrAB and NtrBC two-component systems on the control of carbon and nitrogen utilization in Pseudomonas aeruginosa was characterized by phenotype microarray analyses with single and double mutants and the isogenic parent strain. The tested compounds were clustered based on the growth phenotypes of these strains, and the results clearly demonstrated the pivotal roles of CbrAB and NtrBC in carbon and nitrogen utilization, respectively. Growth of the cbrAB deletion mutant on arginine, histidine, and polyamines used as the sole carbon source was abolished, while growth on the tricarboxylic acid (TCA) cycle intermediates was sustained. In this study, suppressors of the cbr mutant were selected from minimal medium containing l-arginine as the sole carbon and nitrogen source. These mutants fell into two groups according to the ability to utilize histidine. The genomic library of a histidine-positive suppressor mutant was constructed, and the corresponding suppressor gene was identified by complementation as an ntrB allele. Similar results were obtained from four additional suppressor mutants, and point mutations of these ntrB alleles resulting in the following changes in residues were identified, with implications for reduced phosphatase activities: L126W, D227A, P228L, and S229I. The Ntr systems of these ntrB mutants became constitutively active, as revealed by the activity profiles of glutamate dehydrogenase, glutamate synthase, and glutamine synthetase. As a result, these mutants not only regain the substrate-specific induction on catabolic arginine and histidine operons but are also expressed to higher levels than the wild type. While the ΔcbrAB ntrB(Con) mutant restored growth on many N-containing compounds used as the carbon sources, its capability to grow on TCA cycle intermediates and glucose was compromised when ammonium served as the sole nitrogen source, mostly due to an extreme imbalance of carbon and nitrogen regulatory systems. In summary, this study supports the notion that CbrAB and NtrBC form a network to control the C/N balance in P. aeruginosa. Possible molecular mechanisms of these two regulatory elements in the control of arginine and histidine operons used as the model systems are discussed.

scholarly journals Two-component systems required for virulence in Pseudomonas aeruginosa

2017 ◽  
Vol 364 (11) ◽  
Author(s):  
Vanessa I. Francis ◽  
Emma C. Stevenson ◽  
Steven L. Porter
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems
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