Mechanisms of Deficient Innate Immune Responses in Asthma

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Asthma is the most common chronic respiratory disease in the UK. The majority of healthcare costs are related to acute attacks. Acute attacks are also dreaded by asthma sufferers, as they lead to severe breathlessness, hospitalisation or death. Current therapies are not good at either treatment or prevention of acute attacks. New approaches to therapy are therefore urgently needed. Asthma attacks are caused by common cold viruses, which ?go to the chest?, some are also made worse by chronic bacterial colonisation which can be ?reactivated? during acute attacks. We have discovered asthmatics have weak immune responses to viral and bacterial infections, accounting for their increased susceptibility to these infections.
We plan to carry out detailed studies of anti-viral and anti-bacterial immunity in lung cells from adults with asthma, to identify the molecules deficient in switching on immune responses in the lung during these attacks. We will also study different forms of asthma to see how widespread these deficiencies are, and will study children through from birth to 6 years of age, to see when these deficiencies develop. Finally we will see if the deficiencies are detected in blood tests so they can be more easily identified.
By identifying the molecules that are deficient during these attacks, we should be able to identify targets for the development of new therapies for both prevention and treatment of acute attack of asthma. So doing would greatly reduce distress suffered by asthma patients, as well as reducing mortality and health care costs.

Technical Summary

Most asthma morbidity, mortality and health care costs result from acute exacerbations, which are only partially responsive to current therapies. New approaches to treatment are needed. Most exacerbations are associated with rhinovirus infections, but mechanisms of exacerbation are poorly understood. We have reported that atopic asthmatics have increased susceptibility to rhinovirus infection and defective innate immune responses, with deficient rhinovirus-induction of IFN-beta and a novel family of IFNs-lambda1-3 in lower airway cells. Asthmatics also have increased colonisation with Chlamydophila pneumoniae (C.pn) and risk of invasive bacterial infections, C.pn reactivation is linked to asthma exacerbations, alpha/betaIFNs are required for immunity to C.pn, and we have shown LPS induction of IFN-lambda is deficient in asthma. Therefore, IFN deficiency seems an important novel mechanism of increased susceptibility to viral and bacterial infections, which both contribute to asthma exacerbations. Mechanisms of alpha/beta/lambdaIFN deficiency in asthma are unknown ?we seek to understand the mechanisms of deficient IFN production in asthma to identify specific targets for development of new therapies. We need to know whether these deficiencies are asthma/atopy-specific, whether they occur in children and if so, whether they are present at birth or acquired during childhood. We also need to discover if defects are observed in less invasive samples (PBMCs/serum). We hypothesise that IFN deficiency in asthma results from impaired expression/activation of key signalling molecules (from pathogen sensors to transcription factors) required for induction of alpha/beta/lambdaIFNs in response to viral & bacterial infection; that it is a specific feature of asthma (not atopy); it affects cells outside the respiratory tract as well as airway cells and is acquired in the first 5 yrs of life in relation to low exposure to infections (0-3yrs). To investigate these hypotheses, we will study detailed molecular mechanisms of alpha/beta/lambdaIFN induction in response to viral and bacterial infections/stimuli, in primary bronchial epithelial cells, airway macrophages and PBMCs from adults with clearly defined asthma and/or atopy. We will study IFN responses in cells from cord blood and blood taken at 1, 3 & 5 yrs of age in a birth cohort study. IFN production will be related to asthma outcomes determined at 6yrs, and to respiratory infections ascertained in yrs 0-3, along with other relevant risk factors by multiple logistic regression. The proposed studies will identify novel targets for development of new therapies for asthma exacerbations and determine which populations with asthma would be most likely to benefit from new therapies.

Publications

10 25 50
 
Description Asthma UK Professorship
Amount £1,146,793 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 08/2016
 
Description ERC Advanced Grant
Amount £2,000,000 (GBP)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start  
 
Description MRC Programme Grant
Amount £2,019,424 (GBP)
Funding ID P41413 MRC JOHNSTON 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 11/2017
 
Description PREDICTA Post-infectious immune reprogramming and its association with persistence and chronicity of respiratory allergic diseases (6m euros across 13 participants)
Amount £377,932 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2010 
End 09/2015
 
Description AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Characterising the molecular defect in interferon production in asthma.
Collaborator Contribution Characterising the molecular defect in interferon production in asthma.
Impact ....
 
Description Dr Axel Nohturfft, University of London 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description GlaxoSmithKline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Development of an experimental model of rhinovirus induced COPD exacerbation.
Collaborator Contribution Development of an experimental model of rhinovirus induced COPD exacerbation.
Impact ...
 
Description Prof Adnan Custovic, Imperial College London 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Prof Custovic in a study will combining world-leading expertise in infection and immunity, a population based birth cohort study and computational analysis to identify novel mechanisms related to increased susceptibility to asthma, allergies and RTIs.
Collaborator Contribution Collaboration with Prof Custovic in a study will combining world-leading expertise in infection and immunity, a population based birth cohort study and computational analysis to identify novel mechanisms related to increased susceptibility to asthma, allergies and RTIs.
Impact ongoing collaboration
Start Year 2006
 
Description Prof Andrew Bush, Imperial College London 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Anne Greenough, King's College London 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Chris Brightling, University of Leicester 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Joerg Mattes, Newcastle 
Organisation University of Newcastle
Country Australia 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Michael J Holtzman, Washington 
Organisation Washington University in St Louis
Country United States 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Patrick Holt, UWA 
Organisation Telethon Kids Institute
Department Division of Cell Biology
Country Australia 
Sector Charity/Non Profit 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Paul Foster, UCL 
Organisation University of Newcastle
Country Australia 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Peter Sly, UWA 
Organisation University of Queensland
Department Children's Health & Environment Program (CHEP)
Country Australia 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Rene Lutter, AMC 
Organisation VU University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description MRC Centenary Celebration (Science Festival & Open Week, June 2013) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Centre took part in the MRC Centenary Celebrations on 15th-16th June 2013 (Science Festival at the Science Museum) and on 20th June 2013, when we organised a day-time event as part of the Centenary Open Week.


Some outcomes of our Open Day event on 20th June 2013 by the Observation Point in London's South Bank:

• 12ft inflatable lungs from The Roy Castle Lung Cancer Foundation were probably our most significant model for the Open Week event. Centre scientists worked in shifts, presenting the anatomy and function of normal lungs and also spoke of lung diseases
• Asthma themed sand sculptures on the banks of Thames were of great interest. MRC Centenary hash tag #100mrc was also drawn in sand
• The desk size balloon model of lungs demonstrated how lungs work in a healthy individual and what happens in the lungs of asthmatics
• Members of the public were introduced to most common allergens at home ('Allergen House' poster game with magnetic allergens). Allergens such as dustmites and mold were placed in rooms where one would most likely encounter them. Afterwards scientists corrected the answers and explained the reasons why
• We ran an interactive game of Respiratory Olympics where peoples' lung capacities were measured using a spirometer. Men and women competed in different categories and the biggest lung capacity in each category won a prize, which was a pair of tickets to the Open East Festival (the first official opening of the Olympic Park since the 2012 Olympics)
• Overall we felt that our event was very well received, judging by the footfall and the fact that we did not experience many quiet moments. We felt that people were interested in our work and found our research of great significance

Other information:

• Collaboration and interaction with our partners (MRC, Asthma UK, Imperial and King's Colleges) as well as the other London based MRC Centres
• The Biomedical Research Centre (BRC) and the British Society for Immunology (BSI)
• Great learning exposure and enthusiasm for the Centre trainees (students and Post Docs)
• Our Open Day event was attended by Dr. Alfred William Frankland, one of the early pioneers of allergen immunotherapy
• Asthma UK Visit on12th Nov 2013 to the Centre Headquarters. Asthma UK have since requested further events for patients and donors. There are likely to be some as yet unknown impacts.
Year(s) Of Engagement Activity 2013
URL http://www.centenary.mrc.ac.uk/