scholarly journals Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiao Lin ◽  
Joseph M. Pilewski ◽  
Y. Peter Di
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Therapeutic Option ◽  
Bacterial Species ◽  
Acidic Environment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bacterial Response ◽  
Acidic Conditions ◽  
Cf Transmembrane Conductance Regulator ◽  
Neutral Conditions

Pseudomonas aeruginosa is the most prevalent bacterial species that contribute to cystic fibrosis (CF) respiratory failure. The impaired function of CF transmembrane conductance regulator leads to abnormal epithelial Cl–/HCO3– transport and acidification of airway surface liquid. However, it remains unclear why the CF lung is most commonly infected by Pseudomonas aeruginosa versus other pathogens. We carried out studies to investigate if lower pH helps Pseudomonas aeruginosa adapt and thrive in the CF-like acidic lung environment. Our results revealed that Pseudomonas aeruginosa generally forms more biofilm, induces antibiotic resistance faster in acidic conditions, and can be reversed by returning the acidic environment to physiologically neutral conditions. Pseudomonas aeruginosa appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic Pseudomonas aeruginosa infection and colonization.

scholarly journals Cystic Fibrosis Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Qiao Lin ◽  
Joseph M. Pilewski ◽  
Y. Peter Di
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Therapeutic Option ◽  
Bacterial Species ◽  
Acidic Environment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Acidic Conditions ◽  
Neutral Conditions ◽  
Cystic Fibrosis Transmembrane

AbstractPseudomonas aeruginosa is the most prevalent bacterial species that contributes to cystic fibrosis (CF) respiratory failure. The impaired function of cystic fibrosis transmembrane conductance regulator leads to abnormal epithelial Cl− / HCO3− transport and acidification of airway surface liquid. However, it remains unclear why Pseudomonas aeruginosa preferentially colonizes in the CF lungs. In this study, we carried out studies to investigate if lower pH helps Pseudomonas aeruginosa adapt and thrive in the CF-like acidic lung environment. Our results reveal that Pseudomonas aeruginosa generally forms more biofilm and induces antibiotic resistance faster in acidic conditions and that this can be reversed by returning the acidic environment to physiologically neutral conditions. Pseudomonas aeruginosa appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic Pseudomonas aeruginosa infection and colonization.

scholarly journals CFTR-PTEN–dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection

2019 ◽  
Vol 11 (499) ◽  
pp. eaav4634 ◽  
Author(s):  
Sebastián A. Riquelme ◽  
Carmen Lozano ◽  
Ahmed M. Moustafa ◽  
Kalle Liimatta ◽  
Kira L. Tomlinson ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Host Response ◽  
Mitochondrial Activity ◽  
Metabolic Dysfunction ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Functionally Impaired ◽  
Cf Transmembrane Conductance Regulator

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

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 Specific Resistance to Pseudomonas aeruginosa Infection in Zebrafish Is Mediated by the Cystic Fibrosis Transmembrane Conductance Regulator

2010 ◽  
Vol 78 (11) ◽  
pp. 4542-4550 ◽  
Author(s):  
Ryan T. Phennicie ◽  
Matthew J. Sullivan ◽  
John T. Singer ◽  
Jeffrey A. Yoder ◽  
Carol H. Kim
Keyword(s):  
Cystic Fibrosis ◽  
Immune Response ◽  
Pseudomonas Aeruginosa ◽  
Innate Immune Response ◽  
Bacterial Species ◽  
Innate Immune ◽  
Transmembrane Conductance Regulator ◽  
Bacterial Burden ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

ABSTRACT Cystic fibrosis (CF) is a genetic disease caused by recessive mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is associated with prevalent and chronic Pseudomonas aeruginosa lung infections. Despite numerous studies that have sought to elucidate the role of CFTR in the innate immune response, the links between CFTR, innate immunity, and P. aeruginosa infection remain unclear. The present work highlights the zebrafish as a powerful model organism for human infectious disease, particularly infection by P. aeruginosa. Zebrafish embryos with reduced expression of the cftr gene (Cftr morphants) exhibited reduced respiratory burst response and directed neutrophil migration, supporting a connection between cftr and the innate immune response. Cftr morphants were infected with P. aeruginosa or other bacterial species that are commonly associated with infections in CF patients, including Burkholderia cenocepacia, Haemophilus influenzae, and Staphylococcus aureus. Intriguingly, the bacterial burden of P. aeruginosa was found to be significantly higher in zebrafish Cftr morphants than in controls, but this phenomenon was not observed with the other bacterial species. Bacterial burden in Cftr morphants infected with a P. aeruginosa ΔLasR mutant, a quorum sensing-deficient strain, was comparable to that in control fish, indicating that the regulation of virulence factors through LasR is required for enhancement of infection in the absence of Cftr. The zebrafish system provides a multitude of advantages for studying the pathogenesis of P. aeruginosa and for understanding the role that innate immune cells, such as neutrophils, play in the host response to acute bacterial infections commonly associated with cystic fibrosis.

PAR-2-activated secretion by airway gland serous cells: role for CFTR and inhibition by Pseudomonas aeruginosa

2021 ◽  
Vol 320 (5) ◽  
pp. L845-L879
Author(s):  
Derek B. McMahon ◽  
Ryan M. Carey ◽  
Michael A. Kohanski ◽  
Nithin D. Adappa ◽  
James N. Palmer ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Fluid Secretion ◽  
Transmembrane Conductance Regulator ◽  
Contrast Imaging ◽  
Transmembrane Conductance ◽  
Intracellular Ca ◽  
Influx Pathways ◽  
Cf Transmembrane Conductance Regulator ◽  
Protease Activated Receptor 2 ◽  
Conducting Airways

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca2+ imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca2+. At stimulation levels >EC50 for Ca2+, serous cells simultaneously shrank ∼20% over ∼90 s due to KCl efflux reflecting Ca2+-activated Cl− channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (<EC50 for Ca2+), shrinkage was not evident due to failure to activate CaCC. Low levels of cAMP-elevating VIP receptor (VIPR) stimulation, also insufficient to activate secretion alone, synergized with low-level PAR-2 stimulation to elicit fluid secretion dependent on both cAMP and Ca2+ to activate CFTR and K+ channels, respectively. Polarized cultures of primary serous cells also exhibited synergistic fluid secretion. Pre-exposure to Pseudomonas aeruginosa conditioned media inhibited PAR-2 activation by proteases but not peptide agonists in primary nasal serous cells, Calu-3 bronchial cells, and primary nasal ciliated cells. Disruption of synergistic CFTR-dependent PAR-2/VIPR secretion may contribute to reduced airway surface liquid in CF. Further disruption of the CFTR-independent component of PAR-2-activated secretion by P. aeruginosa may also be important to CF pathophysiology.

Liquid secretion inhibitors reduce mucociliary transport in glandular airways

2002 ◽  
Vol 283 (2) ◽  
pp. L329-L335 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Anil Mehta ◽  
Sarah K. Inglis
Keyword(s):  
Beat Frequency ◽  
Anion Channel ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Inhibitory Effects ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Liquid Absorption ◽  
Cf Transmembrane Conductance Regulator

Because of its possible importance in cystic fibrosis (CF) pulmonary pathogenesis, the effect of anion and liquid secretion inhibitors on airway mucociliary transport was examined. When excised porcine tracheas were treated with ACh to induce gland liquid secretion, the rate of mucociliary transport was increased nearly threefold from 2.5 ± 0.5 to 6.8 ± 0.8 mm/min. Pretreatment with both bumetanide and dimethylamiloride (DMA), to respectively inhibit Cl− and HCO[Formula: see text]secretion, significantly reduced mucociliary transport in the presence of ACh by 92%. Pretreatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid similarly reduced mucociliary transport in ACh-treated airways by 97%. These agents did not, however, reduce ciliary beat frequency. Luminal application of benzamil to block liquid absorption significantly attenuated the inhibitory effects of bumetanide and DMA on mucociliary transport. We conclude that anion and liquid secretion is essential for normal mucociliary transport in glandular airways. Because the CF transmembrane conductance regulator protein likely mediates Cl−, HCO[Formula: see text], and liquid secretion in normal glands, we speculate that impairment of gland liquid secretion significantly contributes to defective mucociliary transport in CF.

scholarly journals Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells

2018 ◽  
Vol 314 (4) ◽  
pp. L635-L641 ◽  
Author(s):  
Manon Ruffin ◽  
Lucie Roussel ◽  
Émilie Maillé ◽  
Simon Rousseau ◽  
Emmanuelle Brochiero
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Respiratory Infections ◽  
Bronchial Epithelial Cell ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bronchial Epithelial ◽  
Primary Bronchial Epithelial Cell ◽  
Beneficial Impact

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

scholarly journals Outcomes of early repeat sweat testing in infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID)

2021 ◽  
Author(s):  
vito terlizzi ◽  
Laura Claut ◽  
Carla Colombo ◽  
Antonella Tosco ◽  
Alice Castaldo ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Definitive Diagnosis ◽  
First Year ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Sweat Testing ◽  
Cf Transmembrane Conductance Regulator ◽  
First Year Of Life

Background: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat sweat testing in the first year of life. Methods: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018 and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat sweat testing in the first year of life. Results: Fifty subjects (median age at end of follow-up, 16 months [range, 7–21 months]) were enrolled. Forty-one (82%) had the first sweat chloride in the intermediate range. During follow up, 150 sweat tests were performed (range, 1–7/infant). After a median follow-up of 8.5 months (range 1–16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n=2 [4%]) at 2 and 5 months, respectively; healthy carrier (n=8 [16%]), at a median age of 4 months (range 2–8 months); and healthy (n=1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants. Conclusions: Early repeat sweat testing in the first year of life can shorten the time to definitive diagnosis in screening positive subjects with initial sweat chloride levels in the intermediate range.

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