The role of chronic bacterial airways infection in driving severe asthma

Asthma is the most common chronic lung disease, causing 400,000 deaths around the world every year. It is caused by irritation (or inflammation) of the breathing passages (or airways), producing wheeze, cough, shortness of breath and chest tightness. Up to 10% of sufferers have 'severe asthma' that does not get better despite using inhalers and tablet medications regularly and correctly. These individuals need high doses of several medications including steroids and are at risk of life-threatening 'asthma attacks'. Unfortunately, steroids are not very effective in these people and we are in need of new treatments. Recent research suggests that some people with asthma have damaging bacteria in their airways however we do not know exactly how common this problem is. Until recently tests for identifying these bacteria were not sensitive enough to always detect them. In addition, an exciting new study found that taking a specific, regular antibiotic could reduce asthma attacks in severe asthma. However antibiotics need to be used carefully because of side effects and serious risks of developing resistance. Therefore we need tests which can reliably identify the people most likely to benefit from antibiotics, and we need to understand the mechanisms by which these infections cause such harm in asthma.

Our project will use a sensitive test to help us find out how common bacterial infection is in asthma and pick the right patients to treat with antibiotics, allowing us to target therapy most effectively in the future. To do this we will analyse a large collection of sputum samples from patients in our asthma clinic using standard methods (culture) and compare this with the new techniques (polymerase chain reaction [PCR], DNA sequencing) that give detailed information about bacteria in the airway. The most common damaging bacteria found in the sputum in patients with asthma is called Haemophilus influenzae (H. inf), this bacterium can invade the cells that line the airways and shelter from the body's natural defences against infection, to grow and cause lung inflammation. H. inf can even kill 'neutrophils' one of the most important cells which defend against infection, so the body needs to use other means to clear infection. We want to study these other protective mechanisms to find out how they are weakened in asthma. These mechanisms include recently-discovered mucosal associated invariant T cells or 'MAIT cells', which can identify human cells invaded by bacteria and help them clear infection and potentially even directly kill infected cells. MAIT cells also produce chemicals which help the body to heal.

To study how MAIT cells could be helping the body defend itself against H. inf we will take two complementary approaches. Firstly we will perform bronchoscopies in people with severe asthma - this is a method of examining the airways using a flexible camera called a bronchoscope which is introduced through the mouth or nose and allows us to collect samples of tissue and cells. We can then analyse these samples in great detail and study how MAIT cells are responding to infection. At the same time we can study samples taken of the cells lining the airway to try and find out why they are not as sensitive to steroids in severe asthma. Secondly, we will grow cells that line the airway in the laboratory and infect these with H. inf in order to find out how the infection progresses and also to look at how MAIT cells can become involved to help clear infection.

By developing our understanding of how these important cells respond to threats such as H.inf, we believe that it may be possible to develop future therapies to promote the body's natural responses to clear infection and encourage healing by MAIT cells. This would be a major development in asthma treatment and could also be important for other conditions caused by infection in the airways and lungs.