scholarly journals Role of CFTR, Pseudomonas aeruginosa and Toll-like receptors in cystic fibrosis lung inflammation

2009 ◽  
Vol 37 (4) ◽  
pp. 863-867 ◽  
Author(s):  
Paul J. Buchanan ◽  
Robert K. Ernst ◽  
J. Stuart Elborn ◽  
Bettina Schock
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lipid A ◽  
Treatment Strategies ◽  
Host Interaction ◽  
Genetic Modifications ◽  
Lipid A Structure ◽  
Antimicrobial Peptide Resistance ◽  
Cf Transmembrane Conductance Regulator

CF (cystic fibrosis) is a severe autosomal recessive disease most common in Northwest European populations. Underlying mutations in the CFTR (CF transmembrane conductance regulator) gene cause deregulation of ion transport and subsequent dehydration of the airway surface liquid, producing a viscous mucus layer on the airway surface of CF patients. This layer is readily colonized by bacteria such as Pseudomonas aeruginosa. Owing to the resulting environment and treatment strategies, the bacteria acquire genetic modifications such as antibiotic resistance, biofilm formation, antimicrobial peptide resistance and pro-inflammatory lipid A structures. Lipid A is a component of the lipopolysaccharide cell wall present on bacteria and is recognized by TLR4 (Toll-like receptor 4). Its detection elicits a pro-inflammatory response that is heightened over time due to the addition of fatty acids to the lipid A structure. Eradication of bacteria from the lungs of CF patients becomes increasingly difficult and eventually leads to mortality. In the present review, we describe the role of lipid A as a virulent factor of Ps. aeruginosa; however, it appears that further work is needed to investigate the role of CFTR in the innate immune response and in modifying the pathogen–host interaction.

scholarly journals PmrB Mutations Promote Polymyxin Resistance of Pseudomonas aeruginosa Isolated from Colistin-Treated Cystic Fibrosis Patients

2011 ◽  
Vol 56 (2) ◽  
pp. 1019-1030 ◽  
Author(s):  
Samuel M. Moskowitz ◽  
Mark K. Brannon ◽  
Nandini Dasgupta ◽  
Miyuki Pier ◽  
Nicole Sgambati ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lipid A ◽  
Clinical Isolates ◽  
Gain Of Function ◽  
Content Type ◽  
Regulatory Systems ◽  
Repeated Passage ◽  
High Level

ABSTRACTPseudomonas aeruginosacan develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance,P. aeruginosaisolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-functionpmrBalleles that conferred polymyxin resistance to strains with a wild-type orpmrABdeletion background. Double mutantpmrBalleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutantpmrBalleles induced transcription from the promoter of thearnBoperon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate thatpmrBgain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains ofP. aeruginosa.

scholarly journals Pseudomonas aeruginosa Consumption of Airway Metabolites Promotes Lung Infection

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 957
Author(s):  
Sebastián A. Riquelme ◽  
Alice Prince
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Chronic Disease ◽  
Lung Infection ◽  
Bacterial Disease ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cf Transmembrane Conductance Regulator ◽  
Multiple Pathogens

Prevailing dogma indicates that the lung of cystic fibrosis (CF) individuals is infected by multiple pathogens due to the abundant accumulation of mucus, which traps most of inhaled organisms. However, this hypothesis does not explain how specific opportunists, like Pseudomonas aeruginosa, are selected in the CF lung to cause chronic disease. This strongly suggests that other factors than mucus are accrued in the human airway and might predispose to bacterial disease, especially by P. aeruginosa. In this review we discuss the role of macrophage metabolites, like succinate and itaconate, in P. aeruginosa pneumonia. We analyze how dysfunction of the CF transmembrane conductance regulator (CFTR) favors release of these metabolites into the infected airway, and how P. aeruginosa exploits these elements to induce transcriptomic and metabolic changes that increase its capacity to cause intractable disease. We describe the host and pathogen pathways associated with succinate and itaconate catabolism, mechanisms of bacterial adaptation to these determinants, and suggest how both experimental settings and future therapies should consider macrophage metabolites abundance to better study P. aeruginosa pathogenesis.

scholarly journals PhoQ Mutations Promote Lipid A Modification and Polymyxin Resistance of Pseudomonas aeruginosa Found in Colistin-Treated Cystic Fibrosis Patients

2011 ◽  
Vol 55 (12) ◽  
pp. 5761-5769 ◽  
Author(s):  
Amanda K. Miller ◽  
Mark K. Brannon ◽  
Laurel Stevens ◽  
Helle Krogh Johansen ◽  
Sara E. Selgrade ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lipid A ◽  
Loss Of Function ◽  
Content Type ◽  
Clinical Strains ◽  
Regulatory Systems ◽  
Polymyxin E ◽  
High Level

ABSTRACTPseudomonas aeruginosacan develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of polymyxin resistance (MICs of 8 to 64 mg/liter) in laboratory and clinical strains of this organism. To explore the role of PhoPQ in high-level clinical polymyxin resistance,P. aeruginosastrains with colistin MICs > 512 mg/liter that had been isolated from cystic fibrosis patients treated with inhaled colistin (polymyxin E) were analyzed. Probable loss-of-functionphoQalleles found in these cystic fibrosis strains conferred resistance to polymyxin. Partial and complete suppressor mutations inphoPwere identified in some cystic fibrosis strains with resistance-conferringphoQmutations, suggesting that additional loci can be involved in polymyxin resistance inP. aeruginosa. Disruption of chromosomalphoQin the presence of an intactphoPallele stimulated 4-amino-l-arabinose addition to lipid A and induced transcription from the promoter of thepmrH(arnB) operon, consistent with the known role of this lipid A modification in polymyxin resistance. These results indicate thatphoQloss-of-function mutations can contribute to high-level polymyxin resistance in clinical strains ofP. aeruginosa.

scholarly journals The Phosphoarginine Phosphatase PtpB from Staphylococcus aureus Is Involved in Bacterial Stress Adaptation during Infection

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 645
Author(s):  
Mohamed Ibrahem Elhawy ◽  
Sylvaine Huc-Brandt ◽  
Linda Pätzold ◽  
Laila Gannoun-Zaki ◽  
Ahmed Mohamed Mostafa Abdrabou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Staphylococcus Aureus ◽  
Treatment Strategies ◽  
Physiological Role ◽  
Aureus Strain ◽  
Stress Adaptation ◽  
Cellular Mechanisms ◽  
Host Interaction ◽  
Liver And Kidney

Staphylococcus aureus continues to be a public health threat, especially in hospital settings. Studies aimed at deciphering the molecular and cellular mechanisms that underlie pathogenesis, host adaptation, and virulence are required to develop effective treatment strategies. Numerous host-pathogen interactions were found to be dependent on phosphatases-mediated regulation. This study focused on the analysis of the role of the low-molecular weight phosphatase PtpB, in particular, during infection. Deletion of ptpB in S. aureus strain SA564 significantly reduced the capacity of the mutant to withstand intracellular killing by THP-1 macrophages. When injected into normoglycemic C57BL/6 mice, the SA564 ΔptpB mutant displayed markedly reduced bacterial loads in liver and kidney tissues in a murine S. aureus abscess model when compared to the wild type. We also observed that PtpB phosphatase-activity was sensitive to oxidative stress. Our quantitative transcript analyses revealed that PtpB affects the transcription of various genes involved in oxidative stress adaptation and infectivity. Thus, this study disclosed first insights into the physiological role of PtpB during host interaction allowing us to link phosphatase-dependent regulation to oxidative bacterial stress adaptation during infection.

scholarly journals Repeated isolation of an antibiotic-dependent and temperature-sensitive mutant of Pseudomonas aeruginosa from a cystic fibrosis patient

2020 ◽  
Author(s):  
Daniel J Wolter ◽  
Alison Scott ◽  
Catherine R Armbruster ◽  
Dale Whittington ◽  
John S Edgar ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Lipid A ◽  
Clinical Laboratory ◽  
Membrane Phospholipid ◽  
Growth Defect ◽  
Genetic Mutations ◽  
Temperature Sensitive ◽  
Isolation And Characterization

Abstract Background Bacteria adapt to survive and grow in different environments. Genetic mutations that promote bacterial survival under harsh conditions can also restrict growth. The causes and consequences of these adaptations have important implications for diagnosis, pathogenesis, and therapy. Objectives We describe the isolation and characterization of an antibiotic-dependent, temperature-sensitive Pseudomonas aeruginosa mutant chronically infecting the respiratory tract of a cystic fibrosis (CF) patient, underscoring the clinical challenges bacterial adaptations can present. Methods Respiratory samples collected from a CF patient during routine care were cultured for standard pathogens. P. aeruginosa isolates recovered from samples were analysed for in vitro growth characteristics, antibiotic susceptibility, clonality, and membrane phospholipid and lipid A composition. Genetic mutations were identified by whole genome sequencing. Results P. aeruginosa isolates collected over 5 years from respiratory samples of a CF patient frequently harboured a mutation in phosphatidylserine decarboxylase (psd), encoding an enzyme responsible for phospholipid synthesis. This mutant could only grow at 37°C when in the presence of supplemented magnesium, glycerol, or, surprisingly, the antibiotic sulfamethoxazole, which the source patient had repeatedly received. Of concern, this mutant was not detectable on standard selective medium at 37°C. This growth defect correlated with alterations in membrane phospholipid and lipid A content. Conclusions A P. aeruginosa mutant chronically infecting a CF patient exhibited dependence on sulphonamides and would likely evade detection using standard clinical laboratory methods. The diagnostic and therapeutic challenges presented by this mutant highlight the complex interplay between bacterial adaptation, antibiotics, and laboratory practices, during chronic bacterial infections.

scholarly journals Role of quorum sensing by Pseudomonas aeruginosa in microbial keratitis and cystic fibrosis

Microbiology ◽  
2008 ◽  
Vol 154 (8) ◽  
pp. 2184-2194 ◽  
Author(s):  
M. D. P. Willcox ◽  
H. Zhu ◽  
T. C. R. Conibear ◽  
E. B. H. Hume ◽  
M. Givskov ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Microbial Keratitis

Characterization by pyocine typing and serotyping of oral and sputum strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients

1987 ◽  
Vol 33 (3) ◽  
pp. 221-225 ◽  
Author(s):  
Kunio Komiyama ◽  
Brian F. Habbick ◽  
Tom Martin ◽  
Satwant K. Tumber
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Oral Cavity ◽  
Buccal Mucosa ◽  
Single Strain ◽  
Ecological Sites ◽  
Dental Plaques ◽  
Different Strains

Oral and sputum isolates of Pseudomonas aeruginosa in patients with cystic fibrosis were investigated. Of the 17 patients studied, 12 patients (71%) yielded both mucoid and nonmucoid variants of Pseudomonas aeruginosa from sputum and (or) various oral ecological sites, such as buccal mucosa, tongue dorsum, dental plaques, and saliva. A total of 51 strains of mucoid and nonmucoid Pseudomonas aeruginosa were isolated from these patients and were phenotypically characterized by both pyocine typing and serotyping. Five patients (42%) were colonized or infected by a single strain of Pseudomonas aeruginosa, whereas 7 patients (58%) were cocolonized or coinfected by two or more phenotypically different strains of Pseudomonas aeruginosa. To understand the mechanisms involved in Pseudomonas aeruginosa colonization, it may be necessary to identify multiple isolates of Pseudomonas aeruginosa not only from the sputum but also from the various oral ecological sites and to further explore the role of the oral cavity in this colonization.

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