An investigation of L-ficolin in adult bronchiectasis:- a potential innovative new therapy

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

FIGHTING LUNG INFECTION WITHOUT ANTIBIOTICS
Laennec discovered bronchiectasis in 1819. There are no effective treatments apart from antibiotics for chest infections. With the increasing use of antibiotics there is also increasing antibiotic resistance. This problem has gained widespread media attention, particularly with emerging problems like MRSA, and tackling this is a priority worldwide.
We propose to study an innovative new treatment called L-Ficolin. This is a natural protein made by the liver, which helps to fight bacteria, viruses and fungal infections. Studies in our department have found that 16% of patients with bronchiectasis are deficient in this protein.
In good health the patient‘s own body helps to keep the airways free of infection. Two-thirds of patients with bronchiectasis are permanently infected with bacteria, however, and this leads to daily symptoms of cough, sputum production and chest infections.
We propose a detailed study of L-Ficolin. In the laboratory we will explore the ability of L-Ficolin to help the body to remove bacteria and we will experiment in the laboratory whether treatment with L-Ficolin can help the body to fight infection. This offers a fresh new therapy for this disabling disease, one that is natural and not an antibiotic.
If proven to be of benefit, L-Ficolin may have a role in treating other lung infections such as pneumonia or tuberculosis, two of the leading causes of death worldwide.

Technical Summary

INTRODUCTION: Bronchiectasis is a common disabling chronic lung disease characterized by irreversibly damage with dilatation of the bronchi and persistent microbial colonization of the normally sterile lower respiratory tract. Over 2/3 of patients are chronically colonised with bacteria. Bacterial colonisation is known to perpetuate a vicious cycle of airways inflammation and further tissue damage. Bronchiectasis is associated with significant morbidity, mortality and use of healthcare resources for both children and adults, and new treatments to halt disease progression are needed. Increasing anti-microbial resistance is a major problem worldwide. Novel non-antibiotic therapies for lung infection are needed.
L-ficolin is a recently described pattern recognition receptor and has been shown to promote phagocytosis of Gram-negative and Gram-positive bacteria, fungi, viruses, and particulate allergens.
We found that bronchiectasis was associated with low serum concentrations of L-ficolin (19/118 (16%) compared with 6/170 (3.5%) of controls; P=0.0004). L-ficolin is a recently described soluble protein that is important in the body‘s initial (innate) defense against micro-organisms. Naturally occurring polymorphisms in the L-ficolin gene influence both the production and function of the protein. We aim to determine the role of L-ficolin in bronchiectasis.
HYPOTHESES: (1) Deficiency or impaired function of L-ficolin predisposes to microbial colonization of the airways. (2) Deficiency or impaired function of L-ficolin function leads to impaired clearance of apoptotic inflammatory cells and microbial organisms, which results in persistent airways inflammation.
METHODS: 100 patients will be recruited from a large specialist bronchiectasis clinic (> 300 patients) based at the Royal Infirmary of Edinburgh. Recruitment criteria will include idiopathic/post-infective non-cystic fibrosis bronchiectasis. 50 will be chronically colonised and 50 will be non-colonised. A healthy control group (50 patients) will also be recruited. We will determine the association between L-ficolin and susceptibility to bronchiectasis by analysis of serum and sputum levels of L-ficolin and L-ficolin genetic polymorphisms. We will determine the functionality of L-ficolin in patients‘ sputum by assaying phagocytosis of apoptotic neutrophils by macrophages, microbial adherence to epithelial cells, and microbial phagocytosis and killing. We will explore in vitro how supplementation with L-ficolin can rescue defects seen in these assays.
TRAINING: This project will provide first class training in organizing and running a clinical study, processing sputum and sera, ELISA, cell and bacterial culture, purification of leukocytes from peripheral blood, analysis of apoptosis and phagocytosis, Western blotting, DNA extraction and PCR, and data analysis and presentation.

Publications

10 25 50
 
Description Chief Scientists Office, Project grant
Amount £270,000 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 11/2010 
End 11/2012
 
Description Pathfinder
Amount £712,725 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 12/2019
 
Description Pregnancy zone protein and the lung-investigating gender differences in the lung microbiome
Amount £256,000 (GBP)
Funding ID CAF/16/09 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 02/2017 
End 01/2020
 
Title Biobank of bronchiectasis DNA and blood samples 
Description Over 500 patients have supplied DNA and blood samples to a biobank linked to our clinical bronchiectasis database. This resource will facilitate a number of studies into disease associations and disease modifiers in non-cystic fibrosis bronchiectasis. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact We have already obtained further funding to study single nucleotide polymorphisms associated with bronchiectasis in this cohort and will be able to pursue further studies as a result of the development of this clinical resource. 
 
Title Clinical bronchiectasis cohort database 
Description A large clinical database of patients with non-cystic fibrosis bronchiectasis containing detailed clinical, microbiological and radiological data that will be an invaluable resource for future research 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact We anticipate this resource will provide a wealth of new information that will enhance our understanding of this disease. 
 
Description EMBARC- The European Bronchiectasis Network 
Organisation European Respiratory Society (ERS)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I founded and now chair the European Bronchiectasis Network https:\\www.bronchiectasis.eu
Collaborator Contribution International collaborative network of researchers for translational and clinical research in bronchiectasis
Impact Major output is the iABC consortium, a 60m euro IMI grant for the development of inhaled antibiotics for bronchiectasis
Start Year 2012
 
Description Bronchiectasis patient support group talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 50 patients attended a talk about research into respiratory diseases leading to a wide-ranging discussion about the relevance of research to patients. The patient group have now asked for this to become an annual talk to the group updating them on ongoing research.

Recruitment to respiratory studies has increased and the patient group have asked us to give a regular talk to the patient group about ongoing research.
Year(s) Of Engagement Activity 2011