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Pseudomonas aeruginosa pertenece al género Pseudomonas y es el mayor patógenohumano de este grupo, es invasiva, toxigénica y produce infecciones en humanos(especialmente pacientes inmunodeprimidos)
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Pseudomonas aeruginosa
About Pseudomonas aeruginosagram-negative aerobe bacteriaCommonly found in the environmentAt any moist locationCommon cause of nosocomial infections
P. aeruginosa is an opportunistic pathogenExtremely broad host spectrumHardly any infections in the normal human hostSevere immunodeficiencies and medical devices predispose the patients to P. aeruginosa infectionsBroad spectrum of clinical symptomsUrinary tract infections Pulmonary infectionsSoft tissue infectionsSepsisBone and joint infectionsEndocarditis
P. aeruginosa infectionsP. aeruginosa infections are of particular concern for Cystic fibrosis patientsBurn patientsHospitalised patientsCase mortality rate for patients infected with P. aeruginosa approaches 50%
Nosocomial infectionsFourth most common isolated nosocomial pathogen accounting for approx. 10 % of all hospital acquired infections.Patient-to-patient spread and direct patient contact with environmental reservoirsdisinfectants, respiratory equipment, food, sinks, taps
Diagnosis of P. aeruginosa Isolation and lab identification of the pathogenP. aeruginosa grows well on most laboratory media Identified on the basis of its:Gram morphology, inability to ferment lactose, a positive oxidase reaction, its characteristic odor, its ability to grow at 42 C. Fluorescence is helpful in early identification of P. aeruginosa colonies and may also help identify its presence in wounds.
Treatment of P. aeruginosa infectionsP. aeruginosa is frequently resistant to many commonly used antibiotics. To archive synergy a combination of e.g. gentamicin and carbenicillin is frequently used. No vaccines so far
PathomechanismsAdhesionPili, flagella and fimbriaeInvasionExtracellular enzymes and toxins (proteases, elastase, phospholipases, rhamnolipids, Exotoxin A)DisseminationLeukocidin inhibits neutrophils und leukocytesLPS (Endotoxin)ProtectionCapsule (Alginate)
Interbacterial Communication
McKnight et al, 2000Quorum Sensing in P. aeruginosa
....It is time to close the book on infectious disease.William Stewart, Surgeon in a message to the United State Congress in 1969
Bacterial Biofilms
Biofilms in the environment
Catheter associated biofilms
Chronic biofilm infections
Despite even intensified antibiotic therapy, no eradication of chronic P. aeruginosa infections of the cystic fibrosis lung
Cystic fibrosis Most common life-threatening inherited genetic disorder in the Caucasian population Mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene one in every 25 carry the mutated recessive gene and more than 1 in 4000 live births suffer from CF. Life expectancy: Until the 1930s: the life expectancy of a baby with CF was only a few months, in the 1980s, most deaths from CF occurred in children and teenagers. Today with improved treatments, nearly 40 percent of the CF population is aged 18 and older, for a person with CF the median age of survival is nearly 37 years. Cystic Fibrosis affects a number of organs in the body, cycles of infection and inflammation lead to a progressive deterioration of lung function.
Chronic infection of the Cystic Fibrosis lung
CF and Transplantation Centre 360 patients regularyly attend the CF outpatient clinic at the Medical School Hannover, Germany
Informations of more than 500 CF patients in the local CF register
2000 2005: 100 lung transplantation / year at the MHH
Indications for lung transplantation
Lung Transplantation in Germany
Post lung transplant mortality
Chronic infectious diseasesSlow progressing infectionsFunctional loss of the affected organHighly resistant to host defences and antimicrobial therapy Recovery is rareRole in the development of cancer, peptic ulcer and possibly atherosclerosis
Why is traditional antimicrobial therapy ineffective against biofilm bacteria?
Biofilms, City of microbes
Adaptation and survival is facilitated by diversity
Emergence of morphological distinct niche-specific phenotypes From: Rainey R, Travisano M. Nature, 1998; 39: 69-72
Phenotypic Diversity via the selection of niche-specialists
Small colony variants (SCV)
SCVs of P. aeruginosa in CFSlow growing subpopulations (3% of the P. aeruginosa positive sputum specimens)
SCVs exhibit an increased resistance towards a broad spectrum of antimicrobial agents
The recovery of SCV correlates with parameters revealing poor lung function and an inhalative antimicrobial therapy
Fast growing revertants can be isolated from the SCV population
Auto-aggregation in liquid cultures
M. Rohde, GBF BraunschweigCupA encoded fimbria expression in P. aeruginosa
Molecular Mechanisms controlling the conversion to a SCV biofilm phenotype
Biofilms, City of microbes
Cooperative traits and coordinated behavior of bacteria
McKnight et al, 2000Quorum Sensing in P. aeruginosa
Pseudomonas Quinolone Signal (PQS)
Hydroxy Alkyl QuinolonesPQSHHQ
PQS directly interacts with bacterial DNA in a computed model
PQS enhances iron dependent DNA fragmentationDNA+ PQSDNA+ HHQDNA+ PQS+ Fe(II)DNA+ Fe(II)DNADNAControlDNA+ HHQ+ Fe(II)
PQS enhances the fragmentation of DNA in vivo
PQS production is linked to the release of DNA
PQS non-producing mutantPAO1 wild-type
Regulated DNA release in response to environmental stresses
DNA breakdown products enhance PQS production
Autoinductive PQS production cyclePQSDNApqsA-E transcriptionCell deathPyocyaninPQSLectinRhl Quorum SensingVirulence factorsBiofilm formation
P. aeruginosa WTP. aeruginosa PQS negative MutantePhenotypic Diversity is PQS dependent
Establishment of a chronic state of infection
Chronic InfectionsBiofilmFormationBacterial DiversityInterbacterial Communication
Molecular mechanisms underlying genetic diversityHorizontal gene transfer
Hypermutation
Adaptive mutations
Tiling ArraysMicroarray hybridisation-based method technique to find mutations in bacterial genomes was used to study metronidazole resistance in Helicobacter pylori TJ Albert et al. Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori. Nature Methods 2, 951 - 953 (2005).
Thank You for your attention!
Systems BiologyPrediction of the impact of cellular metabolism on the P. aeruginosa quorum sensing mediated virulence phenotype
Use a theoretical model to complete the knowledge on the system, to plan new experiments and to predict the behavior of the system under changing genetic or environmental conditions
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