Mechanisms, impact and therapeutic targeting of bacterial colonisation in COPD

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

Abstract

Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema and is a very common cause of chronic disability and mortality in the UK. There is an underlying inflammation in the lungs of COPD patients which has so far proved very difficult to treat, so that there is a real need to find more effective treatments in the future. This will depend on better understanding the inflammation that occurs in the lungs of COPD patients, which is usually initiated by cigarette smoking. However, once the disease is established stopping smoking does not clear up the problem so we need to find new and more effective treatments. This grant application brings together some of the key centres for COPD research in the UK to explore a new idea. We know that bacteria (bugs) are present the lungs of COPD patients, unlike the lungs of smokers without COPD and non smokers which are sterile. The presence of these bacteria may drive inflammation, which then results in worsening of the disease and also increases the flare-ups, called exacerbations, which may lead to hospital admission. We believe that this is due to failure to remove bacteria from the lungs and therefore these bacteria grow and cause infections. We have evidence that cells that usually defend the lungs (called macrophages and neutrophils) do not eat up and clear the bacteria as they normally do. In addition, these cells fail to clear all the damaged cells from the lung making the inflammation even worse. We have found that these abnormalities can be explained by abnormal functioning of the macrophages and neutrophils and we have identified some of the mechanisms that have gone wrong. This means that we may be able to find treatments that can restore normal function to these cells so that they can sterilise the lung. This should mean that we can clean up the lung normally, which will lead to a reduction in flare-ups and halting the worsening of the disease. We plan to work closely with several pharmaceutical companies so that we can test any new treatments as soon as possible, so that we may be able to find treatments faster. We hope that this innovative research will therefore lead to new treatment approaches for COPD in the future.

Technical Summary

Lower airway bacterial colonisation (LABC) affects approximately 50% of patients with COPD at all stages of disease and may be important in driving inflammation and impairing the resolution of inflammation. Our central hypothesis is that defective innate and/or adaptive immunity (impaired macrophage and neutrophil phagocytosis and killing of bacteria or humoral and cellular responses) results in failure to clear bacterial and apoptotic cells from the lower airways in smokers who develop COPD. We suggest that the resulting LABC (usually with Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis) drives a persistent inflammatory response, which is resistant to cues for resolution of inflammation. This collaborative application brings together major UK centres with expertise in COPD mechanisms, microbiology and immunology. We aim to explore the links between LABC, chronic inflammation and clinical outcomes, including exacerbation frequency and disease progression in COPD patients. We will determine the prevalence and impact of LABC in COPD patients at all stages of the disease and examine how this may reflect impaired innate immunity and resultant chronic inflammation and altered immune responses. We will elucidate the molecular mechanisms for reduced bacterial phagocytosis and killing reported in alveolar macrophages, monocyte-derived macrophages (MDM) and circulating neutrophils and for the impaired clearance of innate immune cells (efferocytosis) in order to identify novel therapeutic targets. Preliminary studies have identified abnormalities in microtubular stability and sphingosine-1-phosphate signalling in defective bacterial clearance by macrophages that are reversible in-vitro. Delays in macrophage apoptosis also reduce bacterial clearance and can be targeted therapeutically. We will investigate the effect of reducing LABC in COPD patients with antibiotic therapy (oral and inhaled) on inflammation and immune responses as proof-of-concept. Finally, we will perform PoC studies in COPD patients with drugs identified as correcting defective bacterial clearance in COPD cells, including microtubule stabilisers, sphingosine signalling inhibitors and apoptosis modulators. We will study carefully phenotyped COPD patients from existing well characterised cohorts and collaborate closely with other work packages of the consortium. We will interact closely with several industrial partners who have agreed to provide tool compounds, technological skills, data analyses and expertise in trial design. This proposal represents a series of focused and deliverable projects that, through collaborative scientific discovery, will act as a unique platform for therapeutic translation. We believe that exploring LABC and abnormal innate immunity will enhance understanding of disease mechanisms and identify new therapeutic approaches and provide novel biomarkers for the assessment of new treatments.

Publications

10 25 50

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Barnes PJ (2016) Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. in The Journal of allergy and clinical immunology

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Bewley M (2018) Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists in American Journal of Respiratory and Critical Care Medicine

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Bewley MA (2018) Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists. in American journal of respiratory and critical care medicine

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Bewley MA (2017) Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages. in American journal of respiratory and critical care medicine

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Donaldson GC (2013) Factors associated with change in exacerbation frequency in COPD. in Respiratory research

 
Description GOLD Scientific Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Improved management of COPD globally Informing national guideline committees
 
Description Global guidelines for COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Influence on management of COPD worldwide
URL http://www.goldcopd.com/
 
Description Global guidelines for COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Influence on management of COPD worldwide
URL http://www.goldcopd.com/
 
Description Guideline committee
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Global Initiative Chronic Obstructive Lung Disease (GOLD): provides guidelines for diagnosis and management of COPD for an international audience. Member of scientific committee
URL http://goldcopd.org
 
Description COPD MAP: Workpackage 2 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have established a very successful collaboration with University College London (Prof Wisia Wedzicha, Dr Gavin Donaldson), University of Sheffield (Prof Moira Whyte, Dr David Dockrell) and University of Birmingham (Prof Robert Stockley, Dr Liz Sapey) to study bacterial colonisation of the lower airways in patients with COPD. Professor Wedzicha's group has now successfully relocated to Imperial and has been incorporated into Airway Disease Section. We have developed close collaborations with Pfizer (Dr Iain Kilty, Dr Christelle Perros-Huguet), GSK (Dr Ruth Tal-Singer, Dr Edith Hessell) and MedImmune (Dr Matt Robinson).
Collaborator Contribution We have shared and harmonised experimental protocols, trained post-doctoral scientists and technicians and exchanged clinical samples between the centres. Industrial collaborators have provided analytical tools and expertise, including MSD protein analysis, microbiome and data analysis.
Impact No publications yet, but several abstracts have been presented at national and international meetings. ERJ, September 2013, Volume 42, supplement 57 P629 Relationship between monocyte-derived macrophage phagocytosis and airway inflammation in stable COPD R. Singh, K. Chana, K. Such, A. Patel, A. Mackay, D. Garcha, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly P2172 Concordance between airway inflammation and health status in COPD patients with bacterial colonisation R. Singh, A. Mackay, A. Patel, B. Kowlessar, D. Garcha, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha 3301 The species-specific inflammatory response of colonising bacteria in stable COPD R. Singh, A. Patel, A. Mackay, D. Garcha, B. Kowlessar, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha P 3869 Inhibition of p38 mitogen-activated protein kinase has no effect on macrophage phagocytosis of bacteria in patients with COPD M. Bewley, K. Chana, R. Budd, R. Singh, D. Singh, W. Wedzicha, D. Dockrell, M. Whyte, P. J. Barnes, L. Donnelly P3872 Increased susceptibility of M2 monocyte-derived macrophages from COPD patients to oxidative stress K. Such, R. Singh, J. Wedzicha, P. Barnes, L. Donnelly Am J Respir Clin Care Med 2014, volume 189 Sputum Color And The Detection Of Colonizing Bacteria By Quantitative PCR In Stable COPD Richa Singh, , Alexander J. Mackay, Anant R.C. Patel, Davinder S. Garcha, Simon E. Brill, Louise E. Donnelly, Peter J. Barnes, Gavin C. Donaldson, Jadwiga A. Wedzicha: A1017 Alveolar Macrophages From Patients With COPD Have A Defect In Opsonic Phagocytosis Of Streptococcus Pneumoniae M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, D. H. Dockrell, M. K.B. Whyte, Medical Research Council COPD MAP Consortium A1011 Alveolar Macrophages During COPD Demonstrate Reduced Apoptosis-Associated Bacterial Killing And Reduced Mitochondrial Reactive Oxygen Species-Dependent Killing M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, M. K.B. Whyte, D. H. Dockrell, Medical Research Council COPD MAP Consortium A 2862 ERJ, September 2014, Volume 44, Supplement 58 P1479 Oxidative stress drives defective efferocytosis in COPD M2-like macrophages K. Belchamber, R. Singh, J. Wedzicha, M. Whyte, P. Barnes, L. Donnelly 2957 TNFa release by monocyte-derived macrophages at stable and exacerbation states in COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly 3399 Relationship of monocyte-derived macrophage phagocytosis to exacerbation susceptibility in stable COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly
Start Year 2010
 
Description COPD MAP: Workpackage 2 
Organisation University Hospitals Birmingham NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have established a very successful collaboration with University College London (Prof Wisia Wedzicha, Dr Gavin Donaldson), University of Sheffield (Prof Moira Whyte, Dr David Dockrell) and University of Birmingham (Prof Robert Stockley, Dr Liz Sapey) to study bacterial colonisation of the lower airways in patients with COPD. Professor Wedzicha's group has now successfully relocated to Imperial and has been incorporated into Airway Disease Section. We have developed close collaborations with Pfizer (Dr Iain Kilty, Dr Christelle Perros-Huguet), GSK (Dr Ruth Tal-Singer, Dr Edith Hessell) and MedImmune (Dr Matt Robinson).
Collaborator Contribution We have shared and harmonised experimental protocols, trained post-doctoral scientists and technicians and exchanged clinical samples between the centres. Industrial collaborators have provided analytical tools and expertise, including MSD protein analysis, microbiome and data analysis.
Impact No publications yet, but several abstracts have been presented at national and international meetings. ERJ, September 2013, Volume 42, supplement 57 P629 Relationship between monocyte-derived macrophage phagocytosis and airway inflammation in stable COPD R. Singh, K. Chana, K. Such, A. Patel, A. Mackay, D. Garcha, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly P2172 Concordance between airway inflammation and health status in COPD patients with bacterial colonisation R. Singh, A. Mackay, A. Patel, B. Kowlessar, D. Garcha, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha 3301 The species-specific inflammatory response of colonising bacteria in stable COPD R. Singh, A. Patel, A. Mackay, D. Garcha, B. Kowlessar, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha P 3869 Inhibition of p38 mitogen-activated protein kinase has no effect on macrophage phagocytosis of bacteria in patients with COPD M. Bewley, K. Chana, R. Budd, R. Singh, D. Singh, W. Wedzicha, D. Dockrell, M. Whyte, P. J. Barnes, L. Donnelly P3872 Increased susceptibility of M2 monocyte-derived macrophages from COPD patients to oxidative stress K. Such, R. Singh, J. Wedzicha, P. Barnes, L. Donnelly Am J Respir Clin Care Med 2014, volume 189 Sputum Color And The Detection Of Colonizing Bacteria By Quantitative PCR In Stable COPD Richa Singh, , Alexander J. Mackay, Anant R.C. Patel, Davinder S. Garcha, Simon E. Brill, Louise E. Donnelly, Peter J. Barnes, Gavin C. Donaldson, Jadwiga A. Wedzicha: A1017 Alveolar Macrophages From Patients With COPD Have A Defect In Opsonic Phagocytosis Of Streptococcus Pneumoniae M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, D. H. Dockrell, M. K.B. Whyte, Medical Research Council COPD MAP Consortium A1011 Alveolar Macrophages During COPD Demonstrate Reduced Apoptosis-Associated Bacterial Killing And Reduced Mitochondrial Reactive Oxygen Species-Dependent Killing M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, M. K.B. Whyte, D. H. Dockrell, Medical Research Council COPD MAP Consortium A 2862 ERJ, September 2014, Volume 44, Supplement 58 P1479 Oxidative stress drives defective efferocytosis in COPD M2-like macrophages K. Belchamber, R. Singh, J. Wedzicha, M. Whyte, P. Barnes, L. Donnelly 2957 TNFa release by monocyte-derived macrophages at stable and exacerbation states in COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly 3399 Relationship of monocyte-derived macrophage phagocytosis to exacerbation susceptibility in stable COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly
Start Year 2010
 
Description COPD MAP: Workpackage 2 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution We have established a very successful collaboration with University College London (Prof Wisia Wedzicha, Dr Gavin Donaldson), University of Sheffield (Prof Moira Whyte, Dr David Dockrell) and University of Birmingham (Prof Robert Stockley, Dr Liz Sapey) to study bacterial colonisation of the lower airways in patients with COPD. Professor Wedzicha's group has now successfully relocated to Imperial and has been incorporated into Airway Disease Section. We have developed close collaborations with Pfizer (Dr Iain Kilty, Dr Christelle Perros-Huguet), GSK (Dr Ruth Tal-Singer, Dr Edith Hessell) and MedImmune (Dr Matt Robinson).
Collaborator Contribution We have shared and harmonised experimental protocols, trained post-doctoral scientists and technicians and exchanged clinical samples between the centres. Industrial collaborators have provided analytical tools and expertise, including MSD protein analysis, microbiome and data analysis.
Impact No publications yet, but several abstracts have been presented at national and international meetings. ERJ, September 2013, Volume 42, supplement 57 P629 Relationship between monocyte-derived macrophage phagocytosis and airway inflammation in stable COPD R. Singh, K. Chana, K. Such, A. Patel, A. Mackay, D. Garcha, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly P2172 Concordance between airway inflammation and health status in COPD patients with bacterial colonisation R. Singh, A. Mackay, A. Patel, B. Kowlessar, D. Garcha, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha 3301 The species-specific inflammatory response of colonising bacteria in stable COPD R. Singh, A. Patel, A. Mackay, D. Garcha, B. Kowlessar, S. Brill, R. Sapsford, L. Donnelly, P. Barnes, G. Donaldson, J. Wedzicha P 3869 Inhibition of p38 mitogen-activated protein kinase has no effect on macrophage phagocytosis of bacteria in patients with COPD M. Bewley, K. Chana, R. Budd, R. Singh, D. Singh, W. Wedzicha, D. Dockrell, M. Whyte, P. J. Barnes, L. Donnelly P3872 Increased susceptibility of M2 monocyte-derived macrophages from COPD patients to oxidative stress K. Such, R. Singh, J. Wedzicha, P. Barnes, L. Donnelly Am J Respir Clin Care Med 2014, volume 189 Sputum Color And The Detection Of Colonizing Bacteria By Quantitative PCR In Stable COPD Richa Singh, , Alexander J. Mackay, Anant R.C. Patel, Davinder S. Garcha, Simon E. Brill, Louise E. Donnelly, Peter J. Barnes, Gavin C. Donaldson, Jadwiga A. Wedzicha: A1017 Alveolar Macrophages From Patients With COPD Have A Defect In Opsonic Phagocytosis Of Streptococcus Pneumoniae M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, D. H. Dockrell, M. K.B. Whyte, Medical Research Council COPD MAP Consortium A1011 Alveolar Macrophages During COPD Demonstrate Reduced Apoptosis-Associated Bacterial Killing And Reduced Mitochondrial Reactive Oxygen Species-Dependent Killing M. Bewley, R. Budd, D. Singh, P. J. Barnes, L. E. Donnelly, M. K.B. Whyte, D. H. Dockrell, Medical Research Council COPD MAP Consortium A 2862 ERJ, September 2014, Volume 44, Supplement 58 P1479 Oxidative stress drives defective efferocytosis in COPD M2-like macrophages K. Belchamber, R. Singh, J. Wedzicha, M. Whyte, P. Barnes, L. Donnelly 2957 TNFa release by monocyte-derived macrophages at stable and exacerbation states in COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly 3399 Relationship of monocyte-derived macrophage phagocytosis to exacerbation susceptibility in stable COPD R. Singh, K. Belchamber, A. Mackay, B. Kowlessar, J. Allinson, S. Brill, G. Donaldson, P. Barnes, J. Wedzicha, L. Donnelly
Start Year 2010
 
Description Bring Your Child to Work Day at NHLI 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Described in the following website:

http://www1.imperial.ac.uk/nhli/aboutus/child_to_work_day/ -


Great interest in the children. Encouraged discussion of life-work balance between colleagues with children.
Interest to run similar programmes in local schools.
Year(s) Of Engagement Activity 2013,2014,2015
URL http://www1.imperial.ac.uk/nhli/aboutus/child_to_work_day/
 
Description Hakathon for developing new devices for respiratory diseases 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Interactive meeting at Imperial College and beamed to MIT (Cambridge, USA) to discuss new monitoring devices for patients with lung diseases such as COPD. Involved discussion about patients needs with engineers scientists and doctors. Received a lot of national publicity.
Year(s) Of Engagement Activity 2015
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/eventssummary/event_7-9-2015-17-28-1
 
Description Heart & Lung Shop 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Details provided on the following website:
http://www1.imperial.ac.uk/nhli/public_engagement/the_curious_act/heart_and_lung_repair_shops/



High level of interest from the public in participating in clinical trials and in receiving more information. We plan to continue these popular events in the future.
Year(s) Of Engagement Activity 2014
URL http://www1.imperial.ac.uk/nhli/public_engagement/the_curious_act/heart_and_lung_repair_shops/
 
Description Imperial Festival 2012 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Described in the following website:
http://www3.imperial.ac.uk/festival/previousfestivals/imperialfestival2012

Increased public awareness about lung disease, particularly COPD. Engagement of children with a locally devised COPD board game.
Year(s) Of Engagement Activity 2012
URL http://www3.imperial.ac.uk/festival/previousfestivals/imperialfestival2012
 
Description Laboratory Placement for final year school pupils 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 week placement visit to different laboratories and hospital laboratories.
Year(s) Of Engagement Activity 2015
 
Description Patient and volunteer engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact 2 Open Days that invited all patients and normal control subjects to present our research and to get feedback and answer questions from study participants. Very positive feedback from the meeting and more are planned.
Year(s) Of Engagement Activity 2016
 
Description School visit to laboratory 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Visit of 6th form schoolchildren to laboratory to explain our research on respiratory disease
Year(s) Of Engagement Activity 2017