Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity

Shan F. Brunel, Janet A. Willment, Gordon D. Brown, Graham Devereux, Adilia Warris

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Abstract

Aspergillus fumigatus infects up to 50% of cystic fibrosis (CF) patients and may play a role in progressive lung disease. As cystic fibrosis transmembrane conductance regulator is expressed in cells of the innate immune system, we hypothesised that impaired antifungal immune responses play a role in CF-related Aspergillus lung disease. Peripheral blood mononuclear cells, polymorphonuclear cells (PMN) and monocytes were isolated from blood samples taken from CF patients and healthy volunteers. Live-cell imaging and colorimetric assays were used to assess antifungal activity in vitro. Production of reactive oxygen species (ROS) was measured using luminol-induced chemiluminescence and was related to clinical metrics as collected by case report forms. CF phagocytes are as effective as those from healthy controls with regards to phagocytosis, killing and restricting germination of A. fumigatus conidia. ROS production by CF phagocytes was up to four-fold greater than healthy controls (p<0.05). This effect could not be replicated in healthy phagocytes by priming with lipopolysaccharide or serum from CF donors. Increased production of ROS against A. fumigatus by CF PMN was associated with an increased number of clinical exacerbations in the previous year (p=0.007) and reduced lung function (by forced expiratory volume in 1 s) (p=0.014). CF phagocytes mount an intrinsic exaggerated release of ROS upon A. fumigatus stimulation which is associated with clinical disease severity.
Original languageEnglish
Article number00068-2017
Pages (from-to)1-11
Number of pages11
JournalERJ Open Research
Volume4
Issue number2
Early online date9 Apr 2018
DOIs
Publication statusPublished - Apr 2018

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Aspergillus
Phagocytes
Cystic Fibrosis
Superoxides
Aspergillus fumigatus
Reactive Oxygen Species
Lung Diseases
Luminol
Cystic Fibrosis Transmembrane Conductance Regulator
Fungal Spores
Forced Expiratory Volume
Germination
Luminescence
Phagocytosis
Lipopolysaccharides
Monocytes
Immune System
Blood Cells
Healthy Volunteers
Tissue Donors

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Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity. / Brunel, Shan F.; Willment, Janet A.; Brown, Gordon D.; Devereux, Graham; Warris, Adilia.

In: ERJ Open Research, Vol. 4, No. 2, 00068-2017, 04.2018, p. 1-11.

Research output: Contribution to journalArticle

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abstract = "Aspergillus fumigatus infects up to 50{\%} of cystic fibrosis (CF) patients and may play a role in progressive lung disease. As cystic fibrosis transmembrane conductance regulator is expressed in cells of the innate immune system, we hypothesised that impaired antifungal immune responses play a role in CF-related Aspergillus lung disease. Peripheral blood mononuclear cells, polymorphonuclear cells (PMN) and monocytes were isolated from blood samples taken from CF patients and healthy volunteers. Live-cell imaging and colorimetric assays were used to assess antifungal activity in vitro. Production of reactive oxygen species (ROS) was measured using luminol-induced chemiluminescence and was related to clinical metrics as collected by case report forms. CF phagocytes are as effective as those from healthy controls with regards to phagocytosis, killing and restricting germination of A. fumigatus conidia. ROS production by CF phagocytes was up to four-fold greater than healthy controls (p<0.05). This effect could not be replicated in healthy phagocytes by priming with lipopolysaccharide or serum from CF donors. Increased production of ROS against A. fumigatus by CF PMN was associated with an increased number of clinical exacerbations in the previous year (p=0.007) and reduced lung function (by forced expiratory volume in 1 s) (p=0.014). CF phagocytes mount an intrinsic exaggerated release of ROS upon A. fumigatus stimulation which is associated with clinical disease severity.",
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note = "We would like to thank the CF patients for their participation and a special thank you goes to CF nurses Karen Griffiths and Sandra Steele (Aberdeen Royal Infirmary, Aberdeen, UK) for their invaluable contribution to this study. Support statement: A. Warris, G.D. Brown, S.F. Brunel and J.A. Willment were supported by the Wellcome Trust Strategic Award (grant 097377) and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. A. Warris and S.F. Brunel were also supported by the Chloe Fund. Funding information for this article has been deposited with the Crossref Funder Registry.",
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