Elucidating how the respiratory tract microbiota regulate immune responses to bacterial infection

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Chronic obstructive pulmonary disease (COPD) is a common lung disorder that occurs in both smokers and non-smokers. Latest statistics show that COPD affects ~8% of the UK population and the disease is now the 3rd leading cause of death worldwide. Patients with COPD are prone to infections by harmful bacteria that lead to acute symptom flare-ups ('exacerbations'), devastating episodes with a 1 in 4 mortality rate. We urgently need to improve our understanding of why some patients are more susceptible to infections. We could use this understanding to develop new ways of treating the condition with the aim of improving quality of life and outcomes for patients. Recent studies have revealed that the lungs are colonised by millions of resident 'commensal' bacteria (the 'microbiome') which may help to protect against infections triggered by other more harmful bacteria. COPD patients show outgrowth of certain commensals within their microbiome. We do not know whether this outgrowth is just a consequence of the disease or if, by upsetting the immune system, specific commensals actually contribute to increased susceptibility to infection by harmful bacteria.This projects asks the following three questions:1. Do commensals in the lung have a general protective role in preventing infections by harmful bacteria? 2. Do specific changes in the microbiome that occur in COPD reduce the immune system's ability to fight infection by harmful bacteria?3. Could we administer commensals from healthy people into patients with COPD to improve their ability to fight infection by harmful bacteria?This research will be carried out by collaborating scientists at Imperial College and University of Oxford and will take a two-pronged approach to answer these questions. Firstly, the lung microbiome will be studied in a group of patients with COPD to determine if those who have very severe infections by harmful bacteria have outgrowth or reduction of certain commensals. These studies will pinpoint specific commensals that may reduce the immune system's ability to fight harmful bacteria. We will then conduct experiments in mice that are not ethically possible in humans. We will experimentally abolish the lung microbiome with antibiotic treatment and then reintroduce commensals found to be increased in COPD subjects who have severe infections. We will then infect these mice with harmful bacteria and study how commensals affect the immune system's ability to fight off these bacteria. These experiments will allow us to answer whether the microbiome can directly contribute to increased infection susceptibility in COPD. Finally, we will use a mouse model of COPD which mimics many of the microbiome changes seen in patients to determine if administration of 'healthy' commensals can boost the immune system's response to a harmful bacterial infection. It is anticipated that this work will identify important commensals that can directly upset or enhance the immune system. This would then lead to development of new therapies where healthy commensals could be introduced into the lungs of patients with COPD to boost their immune response when exposed to harmful bacteria. In summary, this research will provide new scientific insight into an area of huge clinical importance and facilitate development of exciting new therapies to reduce the burden of disease caused by COPD.