Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701490
Title: Airway bacteria and their relevance to disease severity in asthma
Author: Green, Ben
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2010
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Abstract:
Asthma is a heterogeneous condition resulting from a complex interaction of genetic and environmental factors leading to airway hyperreactivity, reversible bronchoconstriction and chronic airway inflammation. Little is known about the role of chronic bacterial colonization in the underlying inflammation and how it can alter disease phenotype. In COPD, airway colonization with potentially pathogenic microorganisms (PPMs) leads to neutrophilic airways inflammation, increased frequency of exacerbation, worsening symptom scores and an accelerated decline in lung function. The Gram positive coccus Staphylococcus aureus is known to produce enterotoxins (SAEs) which can act as superantigens leading to an exaggerated T lymphocyte response and has been linked to steroid resistance in asthma. Hypotheses tested were: (1) Bacterial colonization patterns differ between the asthmatic and healthy lower airway. (2) Airway colonization with potentially pathogenic bacterial species contributes to asthma severity and alters phenotype. (3) S. aureus colonizes the lower airway in asthma and contributes to treatment resistance through the action of superantigens. The non1culture based, molecular microbiological technique of terminal restriction fragment length polymorphism profiling (T1RFLP) was used to demonstrate the patterns of airway bacterial colonization in severe asthmatics, mild asthmatics and healthy controls. We have demonstrated that T1RFLP profiling of respiratory specimens is a more sensitive tool than standard respiratory culture in detecting potentially pathogenic bacterial species and is able to give a relative abundance of each species compared to the total bacterial load within the specimen. Bronchoalveolar lavage (BAL) was used to sample the distal lower airways of volunteers and demonstrated a more diverse colonizing flora in severe asthmatics than mild asthmatics (p=0.001) and healthy controls (p=0.029). PPMs such as Haemophilus sp. and Streptococcal sp. were more frequently detected in severe asthma than in mild asthma (p<0.001) and healthy controls (p=0.004). The total abundance of PPMs as a percentage of total bacterial load was significantly higher in severe asthmatic BAL than mild asthmatic (p<0.001) and healthy subjects (p=0.004). Within the severe asthma group total BAL PPM abundance correlated with neutrophil counts, IL18 and worsening FEV1. Induced sputum was used to sample the central, proximal, lower airways and demonstrated lower species diversity in severe asthma than in mild asthma (p=0.012) and healthy controls (p=0.005). Within the severe asthma group, when the most abundant species within induced sputum was Haemophilus sp., Streptococcal sp. or Moraxella catarrhalis, significantly worse FEV1 (p=0.025), higher sputum neutrophil counts (p=0.001) and longer disease duration were seen. Dominance of these species within induced sputum was associated with a neutrophilic asthma phenotype (p=0.014). Evidence of the effect of S. aureus superantigens was investigated with BAL T cell receptor (TCR) V? profiling. BAL S. aureus colonization was demonstrated in 38% of severe asthmatic subjects and was associated with higher V? 5.3 (p=0.001), V? 5.1 p=0.01), V? 13.1 (p<0.001) and V? 2 (p=0.022) positive CD4 T cells. This skewing of TCR V? populations provides a surrogate marker for the action of SAEs which may be relevant in the development of steroid resistant disease. The findings of clinically relevant PPM airway colonization in severe asthma provide an opportunity for new targeted therapies in a group of patients where there are currently few therapeutic options.
Supervisor: Howarth, Peter ; Carroll, Mary Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.701490  DOI: Not available
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