The molecular basis of impaired innate immunity to virus infection in asthma

Lead Research Organisation: University of Southampton
Department Name: Inflammation Infection and Repair

Abstract

We are investigating the reasons why common cold viruses make asthma symptoms worse. These periods of worsened symptoms (exacerbations) can be severe enough to cause an increase in the need for medications, and may result in hospitalisation and even death. The most common trigger for these serious exacerbations is a virus infection, such as the common cold. Recently, we have made progress in addressing this problem by demonstrating that the cells that line the airways (epithelial cells) which are the primary target for infection by the common cold virus fail to mount an effective anti-viral response if they are derived from an asthmatic donor. This means that cold viruses are able to replicate more efficiently resulting in lingering lower respiratory tract problems. The purpose of our study is to investigate this defect with a view to identifying novel targets for development of new and effective therapies for virus-induced exacerbations of asthma where there is an unmet clinical need. We also propose to examine the anti-viral response of cells from wheezy and asthmatic children because a defective response in early life may explain the link between viral infections and the onset of asthma.

Technical Summary

Epidemiological studies have linked viral respiratory infection in early life to asthma pathogenesis. Furthermore, the majority of acute asthma exacerbations, especially in children, follow upper respiratory viral infections, of which at least 60% are caused by human rhinoviruses (RV). Despite the increasing frequency of asthma and the associated morbidity, the mechanisms by which RVs may trigger or exacerbate asthma are incompletely understood. Recent studies at the University of Southampton have shown that bronchial epithelial cells (BECs) from asthmatic donors have a defective innate immune response characterized by reduced interferon beta (IFNb) production and reduced apoptosis following infection with RV. These studies provide, for the first time, an explanation for the tendency of asthmatic subjects to have lingering lower respiratory tract problems as a consequence of RV infection.
Recognizing that exacerbations of asthma represent the most severe aspect of this disease and account for a substantial proportion of the health costs both in children and adults, the purpose of the proposed investigation is to test the hypothesis that the impaired innate anti-viral immune response in epithelial cells from asthmatic subjects is a specific defect involving signalling pathways that recognize viral RNA resulting in failure to activate transcription from the IFNb promoter; we further postulate that this defect is an intrinsic or acquired defect that increases the susceptibility of asthmatic children to RV infection.
To test our hypotheses, we will investigate:
a) the immediate response to virus infection by focussing on activation of pathways that recognize dsRNA (TLR3, RIG-1 and PKR) leading to IRF3 activation and transcription of IFNb;
b) the ability of asthmatic epithelial cells to amplify the immediate innate immune response by analyzing autocrine/paracrine stimulation of the type 1 interferon receptor leading to STAT1 activation and transcription of IRF3 and IRF7 leading to sustained expression of type 1 interferons;
c) the potential of compounds that modulate interferon production to protect asthmatic epithelial cells against RV infection;
d) the susceptibility of bronchial epithelial cells from asthmatic children to RV infection in vitro.

These studies have the potential to identify novel targets for development of new and effective therapies for virus-induced exacerbations of asthma where there is an unmet clinical need. Demonstration of a defective innate immune response in asthmatic or wheezy children, will have implications both for treatment of virally-induced exacerbation of asthma in children, and for disease pathogenesis which is strongly associated with respiratory virus infection in early life.

Publications

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Bedke N (2009) Contribution of bronchial fibroblasts to the antiviral response in asthma. in Journal of immunology (Baltimore, Md. : 1950)

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Blume C (2013) In vitro and ex vivo models of human asthma. in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

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Campbell-Harding G (2013) The innate antiviral response upregulates IL-13 receptor a2 in bronchial fibroblasts. in The Journal of allergy and clinical immunology

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Davies DE (2009) The role of the epithelium in airway remodeling in asthma. in Proceedings of the American Thoracic Society

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Djukanovic R (2014) The effect of inhaled IFN-ß on worsening of asthma symptoms caused by viral infections. A randomized trial. in American journal of respiratory and critical care medicine

 
Description A Life Course Approach To Investigating Asthma Pathogenesis And Progression
Amount £2,560,000 (GBP)
Funding ID G0900453 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2015
 
Description COPD MAP collaborative grant year 1
Amount £147,000 (GBP)
Funding ID G1001367/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description COPDMAP continuation
Amount £1,095,618 (GBP)
Funding ID G1001367/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2012 
End 09/2015
 
Description EPSRC EP/G061696/1 Silicon Nanowire Arrays for Viral Infection Markers (NanoTechnology Grand Challenge in Healthcare)
Amount £1,107,763 (GBP)
Funding ID EP/G061696/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start  
 
Description Foundation Grant
Amount £50,000 (GBP)
Funding ID 09/053 
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 01/2011
 
Description Foundation Grant
Amount £49,693 (GBP)
Funding ID 10/060 
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
End 12/2011
 
Description NC3R's Project Grant
Amount £299,000 (GBP)
Funding ID G0700636/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 07/2010
 
Title cell models 
Description We developed a method to culture bronchial epithelial cells obtained from bronchial bushings of normal subjects or those with asthma or COPD. We subsequently refined the protocol to allow for re-differnatition of the cells to recapitulate the in vivo phenotype. We have now extended or protocol to use bronchial brushing obtained by fibreoptic bronchoscopy from paediatric patients undergoing elective surgery (with parental consent). 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2009 
Provided To Others? Yes  
Impact This model has allowed us to identify a defective innate immune response by asthmatic and COPD epithelial cells. This has led to a clinical development programme (being undertaken by Synairgen) to test the potential of inhaled interferon beta to reduce or protect against virus-induced asthma exacerbations 
 
Description BECs 
Organisation Synairgen plc
Country United Kingdom 
Sector Private 
PI Contribution studies of the responses of bronchial fibroblasts to rhinovirus infection.
Collaborator Contribution Provision of primary airway cells for some of our research work.
Impact PubMed ID 19265144
Start Year 2006
 
Description COPDMAP 
Organisation Association of the British Pharmaceutical Industry
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Member of workpage 3
Collaborator Contribution Investigation of the innate immune responses of BECs from COPD patients to rhinovirus infection
Impact Investigation of innate immune dysfunction of airway epithelial cells and the association with responses to oxidative stress.
Start Year 2011
 
Description Viral infection in COPD - Lund 
Organisation Lund University
Department Respiratory Immunopharmacology
Country Sweden 
Sector Academic/University 
PI Contribution Training of Dr Uller in epithelial cell culture and experimental infection. Upon return to Sweden Dr Uller collaborated with Prof Davies who participated in a study undertaken in Sweden by assting with data interpretation and preparation of the manuscript.
Collaborator Contribution 21691053
Impact 21691053
Start Year 2007
 
Description Viral infection in cystic fibrosis 
Organisation University of Cincinnati
Department Perinatal Institute Cincinnati
Country United States 
Sector Academic/University 
PI Contribution We established protocols for growth and differentiation of bronchial epithelial cells from normal
Collaborator Contribution The collaboration has enabled microarray analysis of differentiated epithelial cell cultures from normal and CF children following rhinovirus infection. This has generated substantial datasets for bioinformatic analysiss and data mining.
Impact the collaboration has led to generation of microarray data that will facilitate hypothesis generation
Start Year 2011
 
Company Name Synairgen 
Description Synairgen is a respiratory drug development company with a particular focus on lung antiviral defence in asthma, COPD and severe viral infections. www.synairgen.com 
Year Established 2004 
Impact Synairgen has developed and progressed inhaled interferon beta for virus-induced asthma exacerbations. The company has just announced positive results in a phase II trial. 2014: Licensing deal with AstraZeneca (http://www.astrazeneca.com/Media/Press-releases/Article/20140612-astrazeneca-inlicenses-sng001)
Website http://www.synairgen.com
 
Description lab visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact small groups of visitors visited the lab to learn about our research

help local charity fund raising
Year(s) Of Engagement Activity 2007,2009,2011