The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis.
BACKGROUND
Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear.


OBJECTIVE
To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation.


METHODS
The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis.


RESULTS
We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is the main causative agent. Gt overcame the positive effect of 1,25-OH vitamin D(3) on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomography mosaic pattern consistent with sustained pulmonary function.


CONCLUSIONS
This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Catherine A
CA
Coughlan
Sanjay H
SH
Chotirmall
Julie
J
Renwick
Tidi
T
Hassan
Teck Boon
TB
Low
Gudmundur
G
Bergsson
Ahmed
A
Eshwika
Kathleen
K
Bennett
Katie
K
Dunne
Catherine M
CM
Greene
Cedric
C
Gunaratnam
Kevin
K
Kavanagh
Patrick M
PM
Logan
Philip
P
Murphy
Emer P
EP
Reeves
Noel G
NG
McElvaney
D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use; D001232:Aspergillus fumigatus; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005912:Gliotoxin / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D017964:Itraconazole / Q000627:therapeutic use; D008297:Male; D055732:Pulmonary Aspergillosis / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000378:metabolism; D014132:Trachea / Q000378:metabolism; D055815:Young Adult
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D015848:Interleukin-5; D018167:Receptors, Calcitriol; D017964:Itraconazole; D005912:Gliotoxin