The outlier Pseudomonas aeruginosa strain ATCC 9027 harbors a defective LasR quorum-sensing transcriptional regulator

2020 ◽  
Vol 367 (16) ◽  
Author(s):  
Selene García-Reyes ◽  
Martín P Soto-Aceves ◽  
Miguel Cocotl-Yañez ◽  
Abigail González-Valdez ◽  
Luis Servín-González ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Transcriptional Regulator ◽  
World Health ◽  
Regulatory Sequences ◽  
Strain Atcc ◽  
Research Priority ◽  
Important Health ◽  
Clade 1 ◽  
Health Organization

ABSTRACT Pseudomonas aeruginosa infections represent an important health problem that has been recognized by the World Health Organization as a research priority. A complex regulatory network called the quorum sensing (QS) regulates several P. aeruginosa virulence-related traits, including production of elastase, rhamnolipids and pyocyanin. The avirulent P. aeruginosa strain ATCC 9027 belongs to clade 3, which is the more distant phylogroup in relationship to the other four clades of this species. This strain does not produce QS-regulated virulence factors such as elastase and rhamnolipids when cultured in rich LB medium. We report here that ATCC 9027 harbors a defective LasR protein, presumably due to the presence of an aspartic acid in position 196 instead of a glutamic acid which is the amino acid present in this position in functional LasR proteins of the type strains PAO1 (clade 1) and PA7 (also belonging to clade 3), among others. In addition, we report that ATCC 9027 and PA7 strains present differences compared to the PAO1 strain in lasB which encodes elastase, and in the rhlR regulatory sequences that modify las-boxes, and that these mutations have a little effect in the expression of these genes by a functional LasR transcriptional regulator.

scholarly journals PqsE Is Essential for RhlR-Dependent Quorum Sensing Regulation in Pseudomonas aeruginosa

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Marie-Christine Groleau ◽  
Thays de Oliveira Pereira ◽  
Valérie Dekimpe ◽  
Eric Déziel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Cell Communication ◽  
Transcriptional Regulator ◽  
Homoserine Lactone ◽  
World Health ◽  
Chronic Infections ◽  
Content Type ◽  
Main Regulator ◽  
Health Organization

ABSTRACT The bacterium Pseudomonas aeruginosa has emerged as a central threat in health care settings and can cause a large variety of infections. It expresses an arsenal of virulence factors and a diversity of survival functions, many of which are finely and tightly regulated by an intricate circuitry of three quorum sensing (QS) systems. The las system is considered at the top of the QS hierarchy and activates the rhl and pqs systems. It is composed of the LasR transcriptional regulator and the LasI autoinducer synthase, which produces 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL), the ligand of LasR. RhlR is the transcriptional regulator for the rhl system and is associated with RhlI, which produces its cognate autoinducer C4-HSL. The third QS system is composed of the pqsABCDE operon and the MvfR (PqsR) regulator. PqsABCD synthetize 4-hydroxy-2-alkylquinolines (HAQs), which include ligands activating MvfR. PqsE is not required for HAQ production and instead is associated with the expression of genes controlled by the rhl system. While RhlR is often considered the main regulator of rhlI, we confirmed that LasR is in fact the principal regulator of C4-HSL production and that RhlR regulates rhlI and production of C4-HSL essentially only in the absence of LasR by using liquid chromatography-mass spectrometry quantifications and gene expression reporters. Investigating the expression of RhlR targets also clarified that activation of RhlR-dependent QS relies on PqsE, especially when LasR is not functional. This work positions RhlR as the key QS regulator and points to PqsE as an essential effector for full activation of this regulation. IMPORTANCE Pseudomonas aeruginosa is a versatile bacterium found in various environments. It can cause severe infections in immunocompromised patients and naturally resists many antibiotics. The World Health Organization listed it among the top priority pathogens for research and development of new antimicrobial compounds. Quorum sensing (QS) is a cell-cell communication mechanism, which is important for P. aeruginosa adaptation and pathogenesis. Here, we validate the central role of the PqsE protein in QS particularly by its impact on the regulator RhlR. This study challenges the traditional dogmas of QS regulation in P. aeruginosa and ties loose ends in our understanding of the traditional QS circuit by confirming RhlR to be the main QS regulator in P. aeruginosa. PqsE could represent an ideal target for the development of new control methods against the virulence of P. aeruginosa. This is especially important when considering that LasR-defective mutants frequently arise, e.g., in chronic infections.

scholarly journals Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing

2017 ◽  
Author(s):  
Hovakim Grabski ◽  
Lernik Hunanyan ◽  
Susanna Tiratsuyan ◽  
Hrachik Vardapetyan
Keyword(s):  
Molecular Dynamics ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Principal Component ◽  
Transcriptional Regulator ◽  
Binding Mode ◽  
World Health ◽  
Hydroxyl Group ◽  
Binding Modes

ABSTRACTBackgroundPseudomonas aeruginosais one of the most dangerous superbugs in the list of bacteria for which new antibiotics are urgently needed, which was published by World Health Organization.P. aeruginosais an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants.P. aeruginosaalso forms biofilms. Biofilms increase resistance to antibiotics and host immune responses. Because of biofilms, current therapies are not effective. It is important to find new antibacterial treatment strategies againstP. aeruginosa. Biofilm formation is regulated through a system called quorum sensing. Thus disrupting this system is considered a promising strategy to combat bacterial pathogenicity. It is known that quercetin inhibitsPseudomonas aeruginosabiofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin.ResultsWe used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein ofP. aeruginosawith quercetin. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of quercetin with LasR. We show that quercetin has two binding modes. One binding mode is the interaction with ligand binding domain, this interaction is not competitive and it has also been shown experimentally. The second binding mode is the interaction with the bridge, it involves conservative amino acid interactions from LBD, SLR, and DBD and it is also not competitive. Experimental studies show hydroxyl group of ring A is necessary for inhibitory activity, in our model the hydroxyl group interacts with Leu177 during the second binding mode. This could explain the molecular mechanism of how quercetin inhibits LasR protein.ConclusionsThis study may offer insights on how quercetin inhibits quorum sensing circuitry by interacting with transcriptional regulator LasR. The capability of having two binding modes may explain why quercetin is effective at inhibiting biofilm formation and virulence gene expression.List of abbreviationsPDBProtein data bankMDMolecular DynamicsPCAPrincipal Component AnalysisPCPrincipal ComponentSLRShort Linker RegionBLASTBasic local alignment search toolDBIDavid-Bouldin IndexpsFpseudo-F statistic

scholarly journals A living WHO guideline on drugs to prevent covid-19

BMJ ◽  
2021 ◽  
pp. n526
Author(s):  
François Lamontagne ◽  
Thomas Agoritsas ◽  
Reed Siemieniuk ◽  
Bram Rochwerg ◽  
Jessica Bartoszko ◽  
...  
Keyword(s):  
Systematic Review ◽  
Guideline Development ◽  
Meta Analysis ◽  
World Health ◽  
Policy And Practice ◽  
Assessment Development ◽  
Research Priority ◽  
Health Organization ◽  
Almost All ◽  
Drug Interventions

Abstract Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. Recommendation The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

scholarly journals Revisiting the quorum-sensing hierarchy in Pseudomonas aeruginosa: the transcriptional regulator RhlR regulates LasR-specific factors

Microbiology ◽  
2009 ◽  
Vol 155 (3) ◽  
pp. 712-723 ◽  
Author(s):  
Valérie Dekimpe ◽  
Eric Déziel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Transcriptional Regulator ◽  
Homoserine Lactone ◽  
The Other ◽  
Virulence Determinants ◽  
Late Stationary Phase ◽  
Regulatory Systems ◽  
Specific Factors

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 C4-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-C12-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.

scholarly journals The Ocular Surface and the Coronavirus Disease 2019: Does a Dual ‘Ocular Route’ Exist?

2020 ◽  
Vol 9 (5) ◽  
pp. 1269 ◽  
Author(s):  
Pietro Emanuele Napoli ◽  
Matteo Nioi ◽  
Ernesto d’Aloja ◽  
Maurizio Fossarello
Keyword(s):  
Ocular Surface ◽  
Tear Film ◽  
Underlying Mechanism ◽  
Point Of View ◽  
World Health ◽  
Surface System ◽  
Important Health ◽  
Long Time ◽  
The Moment ◽  
Health Organization

Coronavirus disease 2019 (COVID-19) is an important health problem that was defined as a pandemic by the World Health Organization on 11 March 2020. Although great concern has been expressed about COVID-19 infection acquired through ocular transmission, its underlying mechanism has not currently been clarified. In the current work, we analyzed and elucidated the two main elements that should be taken into account to understand the “ocular route”, both from a clinical and molecular point of view. They are represented by the dynamism of the ocular surface system (e.g., the tear film turnover) and the distribution of ACE2 receptors and TMPRSS2 protein. Although it seems, at the moment, that there is a low risk of coronavirus spreading through tears, it may survive for a long time or replicate in the conjunctiva, even in absence of conjunctivitis signs, indicating that eye protection (e.g., protective goggles alone or in association with face shield) is advisable to prevent contamination from external droplets and aerosol.

scholarly journals Environmental Regulation of Pseudomonas aeruginosa PAO1 Las and Rhl Quorum-Sensing Systems

2007 ◽  
Vol 189 (13) ◽  
pp. 4827-4836 ◽  
Author(s):  
Kangmin Duan ◽  
Michael G. Surette
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Environmental Conditions ◽  
Transcriptional Regulator ◽  
Transcriptional Regulators ◽  
Growth Conditions ◽  
Fine Tuning ◽  
Relative Timing ◽  
Sensing Systems ◽  
Two Systems

ABSTRACT The lasI-lasR and the rhlI-rhlR quorum-sensing systems in Pseudomonas aeruginosa regulate the expression of numerous cellular and secreted virulence factor genes and play important roles in the development of biofilms. The las and rhl systems themselves are known to be directly or indirectly regulated by a number of transcriptional regulators, and consequently, their expression is sensitive to environmental conditions. In this report, the activities of these two quorum-sensing systems have been examined systematically under 46 growth conditions, and the regulation by environmental conditions has been investigated. The relative timing and strength of expression of these two systems varied significantly under different conditions, which contrasts with the notion of a preset hierarchy with these two systems in P. aeruginosa. Depending on the growth conditions, the correlation between each synthase and its cognate transcriptional regulator also varied, suggesting that the transcription of these genes independently allows for further fine tuning of each system. Finally, we observe that the activities of both the lasI-lasR and the rhlI-rhlR quorum-sensing systems were dramatically enhanced in the presence of extracts of sputum samples from cystic fibrosis patients.

scholarly journals The Pseudomonas aeruginosa rmlBDAC operon, encoding dTDP-l-rhamnose biosynthetic enzymes, is regulated by the quorum-sensing transcriptional regulator RhlR and the alternative sigma factor σS

Microbiology ◽  
2012 ◽  
Vol 158 (4) ◽  
pp. 908-916 ◽  
Author(s):  
Marisela Aguirre-Ramírez ◽  
Gerardo Medina ◽  
Abigail González-Valdez ◽  
Victoria Grosso-Becerra ◽  
Gloria Soberón-Chávez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Sigma Factor ◽  
Transcriptional Regulator ◽  
Alternative Sigma Factor ◽  
Biosynthetic Enzymes

scholarly journals Manajemen Perforasi Kornea Pada Pasien Covid-19

2020 ◽  
Vol 7 (1A) ◽  
pp. 195-202
Author(s):  
Ferdian Yanuar ◽  
Hera Dwi Novita ◽  
Herwindo Dicky
Keyword(s):  
Case Report ◽  
Complete Blood Count ◽  
Virus Disease ◽  
Rapid Test ◽  
World Health ◽  
Corneal Perforation ◽  
Operative Care ◽  
Ancillary Test ◽  
Important Health ◽  
Health Organization

Latar Belakang : COVID-19 merupakan masalah kesehatan yang dinyatakan sebagai pandemi oleh WHO. Beberapa penelitian melaporkan tentang hubungan SARS-CoV-2 dengan kelainan pada mata. Pada era pandemi, pengelolaan pasien sakit mata harus hati-hati untuk mencegah penularan petugas medis. Laporan kasus ini menyajikan pengelolaan perforasi kornea pasien terkonfirmasi COVID-19. Metode : Diagnosis ditegakkan berdasarkan anamnesis, pemeriksaan fisik dan oftalmologi dengan pemeriksaan penunjang lainnya. Laporan Kasus : Perempuan berusia 54 tahun dirujuk dengan keluhan keluar darah pada mata kiri sejak 17 jam sebelum sampai RS. Keluhan batuk atau demam 14 hari sebelumnya disangkal. Pada pemeriksaan oftalmologi didapatkan perforasi kornea mata kiri disertai prolaps isi bola mata (iris, vitreus dan choroid). Pada pemeriksaan penunjang didapatkan foto rontgen thorax normal, rapid test covid-19 reaktif dan hasil positif pada PCR dari swab nasofaring. Seluruh staf medis menggunakan alat pelindung diri (APD) tingkat tiga dalam melakukan pemeriksaan fisik maupun penunjang. Dari hasil anamnesis pemeriksaan fisik dan penunjang, pasien didiagnosis dengan perforasi kornea spontan mata kiri dan terkonfirmasi COVID-19. Pasien direncanakan untuk eviserasi mata kiri dengan anestesi umum dan saat tindakan operator dan seluruh staf ruang operasi menggunakan alat pelindung diri (APD) tingkat tiga. Setelah operasi dilakukan, pasien kemudian dirawat di ruang isolasi khusus COVID-19. Swab nasofaring dilakukan ulang sehari setelah operasi dan keesokan harinya. Dua hari setelah operasi, pasien dipulangkan dan isolasi mandiri di rumah Kesimpulan: Laporan kasus ini menunjukkan manajemen perforasi kornea pada pasien terkonfirmasi COVID-19 yang dilakukan sesuai alur khusus termasuk pada pemeriksaan fisik dan penunjang, penegakkan diagnosis oftalmologi dan COVID-19, prosedur pembedahan dan perawatan pasca operasi. Kata Kunci : SARS-CoV-2, Perforasi Kornea, APD, PCR, Eviscerasi   Introduction: Corona-Virus-Disease-2019 (COVID-19) is an important health problem that was defined as a pandemic by the World Health Organization (WHO). There are few reports on the association of SARS-CoV-2 with ocular abnormalities. In the pandemic era, management of ocular patients should be more careful to prevent transmission to medical staff. This report presenting the management of corneal perforation in confirmed COVID-19 patients. Method: The diagnosis was established based on history taking, physical and ophthalmology examination with other ancillary tests. Case Report : 54-year-old female patient referred with complaints of left eye bleeding since 17 hours ago. This patient never complaint about cough or fever 14 days before admission. From the ancillary test (complete blood count and chest x-ray are within normal limit, reactive rapid test for COVID-19, positive result of PCR nasopharynx).  The patient was diagnosed with spontaneous corneal perforation on the left eye with COVID-19 confirmed. The evisceration procedure with general anesthesia was performed with exceptional precaution. Operator and all operating room staff wear the 3rd level of personal protective equipment (PPE). The surgery was successfully done and the patient then hospitalized in the COVID-19 isolated room. Nasopharynx swab performs the day after surgery and the next day after the first swab. Two days after surgery, the patient was discharged and followed by a self-isolation procedure. Conclusion: This case report presenting corneal perforation management in confirmed COVID-19 patients should be performed under a firm scheme including physical and ophthalmological examinations, ophthalmology and COVID-19 diagnosis enforcement, ancillary test, surgery procedure, post-operative care and also PPE utilization. Keyword : SARS-CoV-2, Corneal Perforation, 3rd level PPE, PCR, Evisceration

scholarly journals A study of efficacy of ‘rota virus vaccination’ on morbidity due to rotavirus diarrhoea in children aged 6 months to 5 years

2021 ◽  
Vol 8 (11) ◽  
pp. 1819
Author(s):  
Shreya Agrawal ◽  
Deepak Ugra
Keyword(s):  
Pediatric Intensive Care ◽  
World Health ◽  
High Morbidity ◽  
Rotavirus Vaccine ◽  
Rota Virus ◽  
Significant Difference ◽  
Important Health ◽  
Important Health Issue ◽  
Health Organization ◽  
Children Under 5

Background: Rotavirus diarrhoea was the most common cause of mortality due to diarrhoea among children under 5 years of age. Deaths due to diarrhoea is one of important health issue that needs to be addressed due to high morbidity and mortality associated with it. Rotavirus is recognized as the major cause of hospitalizations among children and it is clear that improvements in hygiene and sanitation alone are not sufficient       to decrease the cases. This study was conducted to assess the efficacy of rotavirus vaccine on morbidity amongst vaccinated and unvaccinated children.Methods: Our study include 40 patients diagnosed with diarrhoea, with stool report positive for rotavirus, with varying degree of dehydration coming to Lilavati Hospital in outpatient department, pediatric ward or pediatric intensive care unit.Results: Out of 40 children, 77.5% of the children vaccinated. We observed the rate of hospitalization was higher 77.8% i.e. 7/9 in the group of unvaccinated children than 45.2% i.e. 14/31 in group of vaccinated children. We found significant difference in the degree of dehydration in vaccinated and unvaccinated children. We found that nearly half of the children in vaccinated group did not have signs of dehydration (belongs to no dehydration category as per World Health Organization scale), while more than 88% of the children in unvaccinated group had some (66.7%) to severe (22.2%) degree of dehydration.Conclusions: Our study concludes that vaccination against rotavirus significantly reduce the morbidity associated with rotavirus diarrhoea as compared to unvaccinated children.

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