Pseudomonas Aeruginosa Infections in Individuals with Cystic Fibrosis

Davidson, Donald J.; Currie, Antony; Speert, David P.

doi:10.1007/978-1-4615-0433-7_5

Cited by 8 publications

(5 citation statements)

References 88 publications

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“…Pseudomonas aeruginosa is an important, opportunistic, multidrug-resistant human pathogen. It is associated with a wide range of serious acute and chronic infections, including ventilator-associated pneumonia and sepsis syndromes, and is the predominant pulmonary infection leading to fatal deterioration of lung function in patients with CF [45]. New interventional approaches for the treatment of P .…”

Section: Discussionmentioning

confidence: 99%

Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

McHugh

Wang

et al. 2019

PLoS Pathog

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Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P . aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P . aeruginosa . We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1β and IL-18 in a manner that is synergistic with P . aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P . aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a “fire alarm” to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.

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Section: Discussionmentioning

confidence: 99%

Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

McHugh

Wang

et al. 2019

PLoS Pathog

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“…In addition, following infection with Pa, defective airway epithelial cell apoptosis, required for pulmonary clearance of this organism [58], has been demonstrated in Cftr tm1Kth and Cftr tm1G551D mice [59]. These observations suggest that careful optimisation may yet enable the development of a model of pulmonary infection with motile Pa, subsequent colonisation, bacterial phenotypic transformation, and fibrotic lung damage, characteristic of human CF disease [60]. However, to date, clear evidence of persistent infection and gross differences in response to Pa have only been achieved using the agar bead model to mimic chronic colonisation, both in Cftr tm1Unc mice [61,62] and Cftr tm1G551D /Cftr tm1G551D mice [63].…”

Section: Pathophysiological Changes In Murine Cf Airwaysmentioning

confidence: 92%

Animal models of cystic fibrosis

Scholte

Davidson

Wilke

et al. 2004

Journal of Cystic Fibrosis

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“…These observations suggest that careful optimization may yet permit the development of an animal model of pulmonary infection with motile P. aeruginosa. These mouse strains may pave the way for an understanding of bacterial colonization, transformation to the mucoid phenotype and fibrotic lung damage having all the characteristics of human CF (Davidson et al 2003).…”

Section: Pathophysiology Of Airway Epithelium In Cf Micementioning

confidence: 99%

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

Kukavica-Ibrulj

Levesque

2008

Lab Anim

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SummaryCystic fibrosis (CF) is caused by a defect in the transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility and severe pulmonary disease. In most patients with CF life expectancy is limited due to a progressive loss of functional lung tissue. Early in life a persistent neutrophylic inflammation can be demonstrated in the airways. The cause of this inflammation, the role of CFTR and the cause of lung morbidity by different CF-specific bacteria, mostly Pseudomonas aeruginosa, are not well understood. The lack of an appropriate animal model with multi-organ pathology having the characteristics of the human form of CF has hampered our understanding of the pathobiology and chronic lung infections of the disease for many years. This review summarizes the main characteristics of CF and focuses on several available animal models that have been frequently used in CF research. A better understanding of the chronic lung infection caused particularly by P. aeruginosa, the pathophysiology of lung inflammation and the pathogenesis of lung disease necessitates animal models to understand CF, and to develop and improve treatment.

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Pseudomonas Aeruginosa Infections in Individuals with Cystic Fibrosis

Cited by 8 publications

References 88 publications

Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

Animal models of cystic fibrosis

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

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