THORACIC
Research type
Research Study
Full title
Establishment of Pseudomonas aeruginosa in the airways of people with cystic fibrosis
IRAS ID
216408
Contact name
Joanne Fothergill
Contact email
Sponsor organisation
University of Liverpool
Duration of Study in the UK
4 years, 11 months, 31 days
Research summary
Research Summary
Cystic fibrosis (CF) is a genetically inherited disease requiring complex life-long medical treatment. People with CF have a shortened life expectancy. The median predicted survival in 2013 was 36.6 years. Although many organs in the body are affected, most morbidity and mortality is due to damage to the lungs caused by long-term bacterial infections requiring extensive treatment with antibiotics. Our previous work has demonstrated that the upper airways are important in the initial stages of bacterial infection. We believe that the upper respiratory tract in patients are key sites in which the bacteria adapts over time, before seeding down to establish in the lungs, and that nasal swabs could therefore be used for the earlier detection of bacterial pathogens. In addition, the use of new, portable sequencing technology (portable Nanopore sequencing) could significantly reduce the time to result from respiratory samples such as respiratory swabs and sputum samples, and permit analysis of sputum samples within the CF clinic, or potentially even at home, reducing the risk of Pseudomonas infection within the clinical environment. This combination of nasal swabbing as an early diagnostic tool and rapid sequencing for the identification of bacteria offers the potential for a prolonged and better targeted window for antibiotic therapy, leading to more successful eradication. The study would involve CF patients attending routine outpatient clinics or inpatients stays. From each patient a sputum sample/respiratory swab and a nasal swab would be taken at each attendance at clinic. The sample collection will be ongoing for up to 2.5 years although we envisage that most samples will be taken in the first year and all analysis will be completed within 5 years. This project could have real impact at a life-changing point in the long term disease management and outlook of CF patients.
Summary of Results
Over half of people with cystic fibrosis (CF) in the UK will have a chronic bacterial lung infection by their late teens. These infections are associated with a more rapid decline in lung function and patients tend to be more ill. We know that infection with one particular bacterium (Pseudomonas aeruginosa, Pa) is worse for people with CF the earlier they get it but if identified quickly, eradication is possible with aggressive antimicrobial treatment. However, the bacteria can adapt to the lung environment and once this happens, it is impossible to eradicate. Exactly how the bacteria adapt in the early stages of infection is poorly understood, but it is clear that the early, pre-adaptation stages of infection could be an attractive therapeutic target to tackle or even prevent both the establishment of infection and the subsequent emergence of antimicrobial resistance.
We have investigated how the bacteria (Pa) adapt and evolve during the early stages of an infection, when they first invade the nose and sinuses. We have identified bacteria that carry mutations. These mutations are commonly found in bacteria from people that have been infected for a long time. We have studied how these mutations change the bacteria and found two mutations that makes the bacteria better at surviving in the lung. This wasn’t known before but both mutations are common in isolates from people with the infection. We have studied how these mutations change the characteristics of the bacteria and found some key processes that they affect. One process is how they interact with host molecules, the other is how the bacteria acquires iron. Iron is essential for survival of bacteria during infections. Previously, both of these genes have been linked with antibiotic resistance but our research has shown that the situation is more complex. These mutations may be a marker of adaptation and provide information about how to prevent adaptation to the lung and the development of chronic infection.
In the second project, we cleaned sputum so we can use direct sequencing to see what microbes were down in the lung. We identified new species and looked at mutations in the population of the most common bacteria P. aeruginosa. We compared this to current diagnostic methods and found that the sequencing gave us more detail and was more consistent.
We looked at how some of these different bacteria interact. We found that some bacteria that seem to have no effect on patients actually change the way that the main bacteria, P. aeruginosa acts. These changes could mean that the bacteria adapts to the lungs quicker and changes how the human body reacts to infection. This information could help us interrupt some of these processes and get rid of infection.REC name
North West - Greater Manchester West Research Ethics Committee
REC reference
17/NW/0091
Date of REC Opinion
28 Feb 2017
REC opinion
Further Information Favourable Opinion