eCite Digital Repository

An antagonist of the platelet-activating factor receptor inhibits streptococcus pneumoniae and non-typeable haemophilus influenzae infection of human bronchial epithelial cells exposed to cigarette smoke

Citation

Shukla, S and Fairbairn, R and Gell, DA and Smith, JA and Walters, EH and O'Toole, RF, An antagonist of the platelet-activating factor receptor inhibits streptococcus pneumoniae and non-typeable haemophilus influenzae infection of human bronchial epithelial cells exposed to cigarette smoke, Thoracic Society of Australia & New Zealand and the Australian & New Zealand Society of Respiratory Science, Annual Scientific Meeting, 1-6 April 2016, Perth, Australia (2016) [Conference Extract]


Preview
PDF (Thoracic Society of Australia & New Zealand and the Australian & New Zealand Society of Respiratory Science, Annual Scientific Meeting Abstracts)
Pending copyright assessment - Request a copy
1Mb
  

Abstract

Introduction/Aim: Epithelial platelet activating factor receptor (PAFr) is a cell adhesion site for specific bacteria, notably the major respiratory pathogens, non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae. We recently published that PAFr expression is upregulated in the airway epithelium of both the large and small airways of smokers and COPD patients. We have also shown that cigarette-smoke extract (CSE) induced PAFr upregulation in vitro. Bacterial cell-wall phosphorylcholine (ChoP) binds specifically to host PAFr expressed on respiratory epithelium. We investigated whether PAFr is a suitable anti-infective target.

Methods: Human bronchial epithelial cells (BEAS-2B) cells were exposed to CSE (1%; 4 h), and adhesion of FITC-tagged S. pneumoniae and NTHi determined. The role of PAFr in mediating adhesion was determined using a known PAFr antagonist, WEB-2086. PAFr expression and fluorescencelabelled bacterial adhesion were assessed by immunofluorescence microscopy. Computer aided image analysis of adherent bacteria was analyzed using Image-Pro Plus 7.0.

Results: BEAS-2B cells exposed to CSE showed significantly increased PAFr expression (P < 0.001). Bacterial adherence was elevated to CSE exposed cells (P < 0.004), as shown by a clinical strain of S. pneumoniae (132), a clinical NTHi strain (RHH3) and a reference-strain of NTHi (NCTC- 4560). Moreover, bacterial adhesion was reduced to untreated control levels with WEB-2086 (P < 0.03), in a dose-dependent manner. A ChoP negative strain of Haemophilus hemolyticus did not show enhanced adherence postCSE treatment and no change after WEB-2086. In silico analyses identified the binding site of WEB-2086 on PAFr and determined new derivatives of WEB-2086 with enhanced predicted binding affinities for the target.

Conclusion: PAFr is a viable therapeutic target against the specific COPD pathogens, S. pneumoniae and NTHi. Increased expression of respiratory epithelial PAFr could be a key factor in the airways of smoking-related COPD patients that increases their risk of acute exacerbated COPD (AECOPD).

Item Details

Item Type:Conference Extract
Keywords:Chronic obstructive pulmonary disease, PAFr, Streptococcus pneumoniae, Haemophilus influenzae
Research Division:Medical and Health Sciences
Research Group:Medical Microbiology
Research Field:Medical Bacteriology
Objective Division:Manufacturing
Objective Group:Human Pharmaceutical Products
Objective Field:Human Pharmaceutical Treatments (e.g. Antibiotics)
Author:Shukla, S (Mr Shakti Shukla)
Author:Gell, DA (Dr David Gell)
Author:Smith, JA (Dr Jeremy Smith)
Author:Walters, EH (Professor Haydn Walters)
Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:107824
Year Published:2016
Deposited By:Medicine (Discipline)
Deposited On:2016-03-25
Last Modified:2016-03-30
Downloads:4 View Download Statistics

Repository Staff Only: item control page