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Article ; Online: Longitudinal changes in the cystic fibrosis airway microbiota with time and treatment.

Einarsson, Gisli G / Sherrard, Laura J / Hatch, Joseph E / Zorn, Bryan / Johnston, Elinor / McGettigan, Clodagh / O'Neill, Katherine / Gilpin, Deirdre F / Downey, Damian G / Murray, Michelle / Lavelle, Gillian / McElvaney, Gerry / Wolfgang, Matthew C / Boucher, Richard / Muhlebach, Marianne S / Bradbury, Ian / Elborn, J Stuart / Tunney, Michael M

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

2023

Abstract: Background: Whether there is any benefit in integrating culture-independent molecular analysis of the lower airway microbiota of people with cystic fibrosis into clinical care is unclear. This study determined the longitudinal trajectory of the ... ...

Abstract	Background: Whether there is any benefit in integrating culture-independent molecular analysis of the lower airway microbiota of people with cystic fibrosis into clinical care is unclear. This study determined the longitudinal trajectory of the microbiota and if there were microbiota characteristics that corresponded with response to treatment or predicted a future pulmonary exacerbation. Methods: At least one sputum sample was collected from 149 participants enrolled in this prospective longitudinal multi-centre study and total bacterial density and microbiota community measurements were determined and compared with clinical parameters. Results: In 114 participants with paired samples when clinically stable, ∼8 months apart, the microbiota remained conserved between timepoints, regardless of whether participants received acute intravenous antibiotic treatment or not. In 62 participants, who presented with an acute exacerbation, a decrease in community richness correlated best with patient response to antibiotic treatment. Analysis of baseline samples from 30 participants who exacerbated within 4 months of their stable sample being collected and 72 participants who remained stable throughout the study showed that community characteristics such as lower richness at baseline may be predictive of an exacerbation in addition to several clinical parameters. However, lasso regression analysis indicated that only lung function (p = 0.014) was associated with a future exacerbation. Conclusions: The airway microbiota remains stable over periods <1 year with modest shifts related to treatment apparent which might provide some additional insights to patient-level measurements.
Language	English
Publishing date	2023-12-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2084724-5
ISSN	1873-5010 ; 1569-1993
ISSN (online)	1873-5010
ISSN	1569-1993
DOI	10.1016/j.jcf.2023.11.010
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Article ; Online: Caspase-11-Mediated Cell Death Contributes to the Pathogenesis of Imiquimod-Induced Psoriasis.

Kenealy, Sinéad / Manils, Joan / Raverdeau, Mathilde / Munoz-Wolf, Natalia / Barber, Gillian / Liddicoat, Alex / Lavelle, Ed C / Creagh, Emma M

The Journal of investigative dermatology

2019 Volume 139, Issue 11, Page(s) 2389–2393.e3

MeSH term(s)	Animals ; Caspases, Initiator/genetics ; Caspases, Initiator/metabolism ; Cell Death ; Cell Proliferation ; Disease Models, Animal ; Humans ; Imiquimod ; Inflammation/metabolism ; Inflammation/pathology ; Interleukin-1beta/metabolism ; Mice ; Mice, Knockout ; Neovascularization, Pathologic ; Psoriasis/chemically induced ; Psoriasis/metabolism ; Psoriasis/pathology ; Ribonuclease, Pancreatic/genetics ; Ribonuclease, Pancreatic/metabolism ; Skin/metabolism ; Skin/pathology
Chemical Substances	Interleukin-1beta ; Ang2 protein, mouse (EC 3.1.27.5) ; Ribonuclease, Pancreatic (EC 3.1.27.5) ; Casp4 protein, mouse (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-) ; Imiquimod (P1QW714R7M)
Language	English
Publishing date	2019-06-05
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2019.05.010
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Article ; Online: Reply.

Lavelle, Gillian M / Mirković, Bojana / Chotirmall, Sanjay H / McElvaney, Noel G

The Journal of allergy and clinical immunology

2016 Volume 137, Issue 3, Page(s) 969–970

MeSH term(s)	Aspergillosis/etiology ; Aspergillosis/metabolism ; Aspergillus/immunology ; Basophils/metabolism ; Cystic Fibrosis/complications ; Female ; Humans ; Male ; Phosphoric Diester Hydrolases/metabolism ; Pyrophosphatases/metabolism
Chemical Substances	Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Pyrophosphatases (EC 3.6.1.-)
Language	English
Publishing date	2016-03
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2015.11.013
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Article ; Online: Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences.

Lavelle, Gillian M / White, Michelle M / Browne, Niall / McElvaney, Noel G / Reeves, Emer P

BioMed research international

2016 Volume 2016, Page(s) 5258727

Abstract: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic ... ...

Abstract	Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF.
MeSH term(s)	Animals ; Cystic Fibrosis/genetics ; Cystic Fibrosis/physiopathology ; Cystic Fibrosis Transmembrane Conductance Regulator/biosynthesis ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Disease Models, Animal ; Ferrets/genetics ; Humans ; Inflammation/genetics ; Inflammation/physiopathology ; Mice ; Neutrophils/pathology ; Swine/genetics
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Keywords	covid19
Language	English
Publishing date	2016-06-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2016/5258727
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Article ; Online: Immunoevasive Aspergillus virulence factors.

Chotirmall, Sanjay H / Mirkovic, Bojana / Lavelle, Gillian M / McElvaney, Noel G

Mycopathologia

2014 Volume 178, Issue 5-6, Page(s) 363–370

Abstract: Individuals with structural lung disease or defective immunity are predisposed to Aspergillus-associated disease. Manifestations range from allergic to cavitary or angio-invasive syndromes. Despite daily spore inhalation, immunocompetence facilitates ... ...

Abstract	Individuals with structural lung disease or defective immunity are predisposed to Aspergillus-associated disease. Manifestations range from allergic to cavitary or angio-invasive syndromes. Despite daily spore inhalation, immunocompetence facilitates clearance through initiation of innate and adaptive host responses. These include mechanical barriers, phagocyte activation, antimicrobial peptide release and pattern recognition receptor activation. Adaptive responses include Th1 and Th2 approaches. Understanding Aspergillus virulence mechanisms remains critical to the development of effective research and treatment strategies to counteract the fungi. Major virulence factors relate to fungal structure, protease release and allergens; however, mechanisms utilized to evade immune recognition continue to be important in establishing infection. These include the fungal rodlet layer, dihydroxynaphthalene-melanin, detoxifying systems for reactive oxygen species and toxin release. One major immunoevasive toxin, gliotoxin, plays a key role in mediating Aspergillus-associated colonization in the context of cystic fibrosis. Here, it down-regulates vitamin D receptor expression which following itraconazole therapy is rescued concurrent with decreased Th2 cytokine (IL-5 and IL-13) concentrations in the CF airway. This review focuses on the interaction between Aspergillus pathogenic mechanisms, host immune responses and the immunoevasive strategies employed by the organism during disease states such as that observed in cystic fibrosis.
MeSH term(s)	Aspergillosis/immunology ; Aspergillosis/microbiology ; Aspergillus/growth & development ; Aspergillus/immunology ; Humans ; Immune Evasion ; Virulence Factors/metabolism
Chemical Substances	Virulence Factors
Language	English
Publishing date	2014-06-28
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	391081-7
ISSN	1573-0832 ; 0369-299X ; 0301-486X ; 0027-5530
ISSN (online)	1573-0832
ISSN	0369-299X ; 0301-486X ; 0027-5530
DOI	10.1007/s11046-014-9768-y
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Article ; Online: Animal Models of Cystic Fibrosis Pathology

Gillian M. Lavelle / Michelle M. White / Niall Browne / Noel G. McElvaney / Emer P. Reeves

BioMed Research International, Vol

Phenotypic Parallels and Divergences

2016 Volume 2016

Abstract	Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF.
Keywords	Medicine ; R
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
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Article ; Online: Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease.

White, Michelle M / Geraghty, Patrick / Hayes, Elaine / Cox, Stephen / Leitch, William / Alfawaz, Bader / Lavelle, Gillian M / McElvaney, Oliver J / Flannery, Ryan / Keenan, Joanne / Meleady, Paula / Henry, Michael / Clynes, Martin / Gunaratnam, Cedric / McElvaney, Noel G / Reeves, Emer P

EBioMedicine

2017 Volume 23, Page(s) 173–184

Abstract: Background: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences ... ...

Abstract	Background: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. Methodology: PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays. Findings: Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. Interpretation: Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion.
Language	English
Publishing date	2017-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2017.08.013
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Article ; Online: Aspergillus-associated airway disease, inflammation, and the innate immune response.

Chotirmall, Sanjay H / Al-Alawi, Mazen / Mirkovic, Bojana / Lavelle, Gillian / Logan, P Mark / Greene, Catherine M / McElvaney, Noel G

BioMed research international

2013 Volume 2013, Page(s) 723129

Abstract: Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical ... ...

Abstract	Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit.
MeSH term(s)	Animals ; Aspergillus/immunology ; Humans ; Immunity, Innate/immunology ; Lung/immunology ; Models, Immunological ; Pneumonia/immunology ; Pneumonia/microbiology ; Pulmonary Aspergillosis/immunology ; Pulmonary Aspergillosis/microbiology
Language	English
Publishing date	2013-07-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2013/723129
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Article ; Online: Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study.

Muhlebach, Marianne S / Hatch, Joseph E / Einarsson, Gisli G / McGrath, Stef J / Gilipin, Deirdre F / Lavelle, Gillian / Mirkovic, Bojana / Murray, Michelle A / McNally, Paul / Gotman, Nathan / Davis Thomas, Sonia / Wolfgang, Matthew C / Gilligan, Peter H / McElvaney, Noel G / Elborn, J Stuart / Boucher, Richard C / Tunney, Michael M

The European respiratory journal

2018 Volume 52, Issue 1

Abstract: Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). ...

Abstract	Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities.
MeSH term(s)	Adolescent ; Adult ; Aged ; Anti-Bacterial Agents/therapeutic use ; Bacteria, Anaerobic/classification ; Bacteria, Anaerobic/isolation & purification ; Bacterial Infections/diagnosis ; Bacterial Infections/drug therapy ; Child ; Child, Preschool ; Cystic Fibrosis/microbiology ; Cystic Fibrosis/physiopathology ; Female ; Humans ; Infant ; Internationality ; Logistic Models ; Male ; Microbiota ; Middle Aged ; Multivariate Analysis ; Respiratory System/microbiology ; Sputum/microbiology ; Young Adult
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2018-07-11
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.00242-2018
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Zs.A 2322: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Chitinase activation in patients with fungus-associated cystic fibrosis lung disease.

Hector, Andreas / Chotirmall, Sanjay H / Lavelle, Gillian M / Mirković, Bojana / Horan, Deirdre / Eichler, Laura / Mezger, Markus / Singh, Anurag / Ralhan, Anjai / Berenbrinker, Sina / Mack, Ines / Ensenauer, Regina / Riethmüller, Joachim / Graepler-Mainka, Ute / Murray, Michelle A / Griese, Matthias / McElvaney, N Gerry / Hartl, Dominik

The Journal of allergy and clinical immunology

2016 Volume 138, Issue 4, Page(s) 1183–1189.e4

Abstract: Background: Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)-associated lung disease remains ... ...

Abstract	Background: Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)-associated lung disease remains unclear. Objective: The aim of this study was to assess chitinase activity systemically and in the airways of patients with CF and asthma compared with healthy subjects. Additionally, we assessed factors that regulate chitinase activity within the lungs of patients with CF. Methods: Chitinase activities were quantified in serum and bronchoalveolar lavage fluid from patients with CF, asthmatic patients, and healthy control subjects. Mechanistically, the role of CF airway proteases and genetic chitinase deficiency was assessed. Results: Chitinase activity was systemically increased in patients with CF compared with that in healthy control subjects and asthmatic patients. Further stratification showed that chitinase activity was enhanced in patients with CF colonized with Candida albicans compared with that in noncolonized patients. CF proteases degraded chitinases in the airway microenvironment of patients with CF. Genetic chitinase deficiency was associated with C albicans colonization in patients with CF. Conclusion: Patients with CF have enhanced chitinase activation associated with C albicans colonization. Therefore chitinases might represent a novel biomarker and therapeutic target for CF-associated fungal disease.
MeSH term(s)	Adolescent ; Adult ; Asthma/complications ; Candida albicans/isolation & purification ; Candida albicans/metabolism ; Candidiasis/complications ; Candidiasis/enzymology ; Chitinases/blood ; Chitinases/deficiency ; Chitinases/genetics ; Chitinases/metabolism ; Cystic Fibrosis/complications ; Cystic Fibrosis/microbiology ; Female ; Humans ; Male ; Up-Regulation ; Young Adult
Chemical Substances	Chitinases (EC 3.2.1.14)
Language	English
Publishing date	2016-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2016.01.031
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