Ivacaftor restores delayed mucociliary transport caused by Pseudomonas aeruginosa– induced acquired cystic fibrosis transmembrane conductance regulator dysfunction in rabbit nasal epithelia

2021 ◽  
Author(s):  
Do‐Yeon Cho ◽  
Shaoyan Zhang ◽  
Daniel F. Skinner ◽  
Dong Jin Lim ◽  
Catherine Banks ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

S3-Leitlinie: Lungenerkrankung bei Mukoviszidose – Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa

Pneumologie ◽  
2018 ◽  
Vol 72 (05) ◽  
pp. 347-392 ◽  
Author(s):  
C. Schwarz ◽  
B. Schulte-Hubbert ◽  
J. Bend ◽  
M. Abele-Horn ◽  
I. Baumann ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Medikamentöse Therapie ◽  
Transmembrane Conductance Regulator ◽  
Wird Eine ◽  
Transmembrane Conductance ◽  
Diagnostik Und Therapie ◽  
Cystic Fibrosis Transmembrane

ZusammenfassungMukoviszidose (Cystic Fibrosis, CF) ist die häufigste, autosomal-rezessiv vererbte Multisystemerkrankung. In Deutschland sind ca. 8000 Menschen betroffen. Die Erkrankung wird durch Mutationen im Cystic Fibrosis Transmembrane Conductance Regulator (CFTR-) Gen verursacht; diese führen zu einer Fehlfunktion des Chloridkanals CFTR. Dadurch kommt es in den Atemwegen zu einer unzureichenden Hydrierung des epithelialen Flüssigkeitsfilms und somit zu einer chronischen Inflammation. Rezidivierende Infektionen der Atemwege sowie pulmonale Exazerbationen der Lunge führen im Verlauf zu zunehmender Inflammation, pulmonaler Fibrose und fortschreitender Lungendestruktion bis hin zur respiratorischen Globalinsuffizienz, die für über 90 % der Mortalität verantwortlich ist. Das Ziel der medikamentösen Therapie ist die pulmonale Inflammation und v. a. die Infektion der Atemwege zu reduzieren. Der Kolonisation und chronischen Infektion mit Pseudomonas aeruginosa (Pa) kommt die größte Bedeutung zu. Diese führt zu weiterem Verlust an Lungenfunktion. Für die medikamentöse Therapie der chronischen Pa-Infektion stehen viele unterschiedliche Therapieoptionen zur Verfügung.Mit dieser S3-Leitlinie wird eine einheitliche Definition für die chronische Pa-Infektion implementiert sowie eine evidenzbasierte Diagnostik und Therapie dargelegt, um eine Orientierung bei der individuellen Therapieentscheidung zu geben.

scholarly journals Pseudomonas aeruginosa-Induced Bleb-Niche Formation in Epithelial Cells Is Independent of Actinomyosin Contraction and Enhanced by Loss of Cystic Fibrosis Transmembrane-Conductance Regulator Osmoregulatory Function

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Amber L. Jolly ◽  
Desire Takawira ◽  
Olufolarin O. Oke ◽  
Sarah A. Whiteside ◽  
Stephanie W. Chang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Opportunistic Pathogen ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Content Type ◽  
Bleb Formation ◽  
Niche Formation ◽  
Cystic Fibrosis Transmembrane

ABSTRACTThe opportunistic pathogenPseudomonas aeruginosacan infect almost any site in the body but most often targets epithelial cell-lined tissues such as the airways, skin, and the cornea of the eye. A common predisposing factor is cystic fibrosis (CF), caused by defects in the cystic fibrosis transmembrane-conductance regulator (CFTR). Previously, we showed that when P. aeruginosa enters epithelial cells it replicates intracellularly and occupies plasma membrane blebs. This phenotype is dependent on the type 3 secretion system (T3SS) effector ExoS, shown by others to induce host cell apoptosis. Here, we examined mechanisms for P. aeruginosa-induced bleb formation, focusing on its relationship to apoptosis and the CFTR. The data showed that P. aeruginosa-induced blebbing in epithelial cells is independent of actin contraction and is inhibited by hyperosmotic media (400 to 600 mOsM), distinguishing bacterially induced blebs from apoptotic blebs. Cells with defective CFTR displayed enhanced bleb formation upon infection, as demonstrated using bronchial epithelial cells from a patient with cystic fibrosis and a CFTR inhibitor, CFTR(Inh)-172. The defect was found to be correctable either by incubation in hyperosmotic media or by complementation with CFTR (pGFP-CFTR), suggesting that the osmoregulatory function of CFTR counters P. aeruginosa-induced bleb-niche formation. Accordingly, and despite their reduced capacity for bacterial internalization, CFTR-deficient cells showed greater bacterial occupation of blebs and enhanced intracellular replication. Together, these data suggest that P. aeruginosa bleb niches are distinct from apoptotic blebs, are driven by osmotic forces countered by CFTR, and could provide a novel mechanism for bacterial persistence in the host.IMPORTANCEPseudomonas aeruginosais an opportunistic pathogen problematic in hospitalized patients and those with cystic fibrosis (CF). Previously, we showed that P. aeruginosa can enter epithelial cells and replicate within them and traffics to the membrane blebs that it induces. This “bleb-niche” formation requires ExoS, previously shown to cause apoptosis. Here, we show that the driving force for bleb-niche formation is osmotic pressure, differentiating P. aeruginosa-induced blebs from apoptotic blebs. Either CFTR inhibition or CFTR mutation (as seen in people with CF) causes P. aeruginosa to make more bleb niches and provides an osmotic driving force for blebbing. CFTR inhibition also enhances bacterial occupation of blebs and intracellular replication. Since CFTR is targeted for removal from the plasma membrane when P. aeruginosa invades a healthy cell, these findings could relate to pathogenesis in both CF and healthy patient populations.

scholarly journals Ivacaftor, a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator, Enhances Ciprofloxacin Activity Against Pseudomonas aeruginosa

2018 ◽  
Vol 33 (2) ◽  
pp. 129-136 ◽  
Author(s):  
Do-Yeon Cho ◽  
Dong Jin Lim ◽  
Calvin Mackey ◽  
Daniel Skinner ◽  
Shaoyan Zhang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Crystal Violet ◽  
Laser Scanning Microscopy ◽  
Transmembrane Conductance Regulator ◽  
Crystal Violet Staining ◽  
Transmembrane Conductance ◽  
Planktonic Growth ◽  
Cystic Fibrosis Transmembrane

Background Methods to improve the clinical efficacy of currently available antibiotics against multidrug resistant bacteria in cystic fibrosis (CF) chronic rhinosinusitis (CRS) are greatly needed. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, was recently identified as having potentially beneficial off-target effects as a weak inhibitor of bacterial DNA gyrase and topoisomerase IV. The objective of the current study is to evaluate whether ivacaftor enhances the antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa. Methods The planktonic growth of the PAO-1 strain of P. aeruginosa was studied in the presence of ciprofloxacin and/or ivacaftor. Effects were measured according to optical density of cultured PAO-1 at 600 nm. For a static PAO-1 biofilm assay, the PAO-1 strain was inoculated and cultured for 72 h in the presence of the drugs. Formed PAO-1 biofilms were quantified by crystal violet staining and imaged with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Results PAO-1 growth was significantly reduced in the presence of ivacaftor (8 or 16 µg/mL) and ciprofloxacin (0.02 or 0.05 µg/mL) compared to ciprofloxacin alone ( P < .001). Similarly, ivacaftor (8 or 16 µg/mL) showed a significant reduction of PAO-1 biofilms when treated with 0.05 µg/mL of ciprofloxacin. Significant synergism was noted between ciprofloxacin and 16 µg/mL of ivacaftor ( P < .0001) in reducing planktonic growth and biofilm formation. Quantitative measurements with crystal violet staining were correlated to CLSM and SEM images. Conclusion Ivacaftor enhanced ciprofloxacin’s antimicrobial activity against P. aeruginosa. Further studies evaluating the efficacy of ivacaftor/ciprofloxacin combination for P. aeruginosa for CF CRS are warranted.

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.

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