Mechanisms of Deficient Innate Immune Responses in Asthma

Asthma is the most common chronic respiratory disease in the UK. The majority of healthcare costs are related to acute attacks. Acute attacks are also dreaded by asthma sufferers, as they lead to severe breathlessness, hospitalisation or death. Current therapies are not good at either treatment or prevention of acute attacks. New approaches to therapy are therefore urgently needed. Asthma attacks are caused by common cold viruses, which ?go to the chest?, some are also made worse by chronic bacterial colonisation which can be ?reactivated? during acute attacks. We have discovered asthmatics have weak immune responses to viral and bacterial infections, accounting for their increased susceptibility to these infections.
We plan to carry out detailed studies of anti-viral and anti-bacterial immunity in lung cells from adults with asthma, to identify the molecules deficient in switching on immune responses in the lung during these attacks. We will also study different forms of asthma to see how widespread these deficiencies are, and will study children through from birth to 6 years of age, to see when these deficiencies develop. Finally we will see if the deficiencies are detected in blood tests so they can be more easily identified.
By identifying the molecules that are deficient during these attacks, we should be able to identify targets for the development of new therapies for both prevention and treatment of acute attack of asthma. So doing would greatly reduce distress suffered by asthma patients, as well as reducing mortality and health care costs.

Most asthma morbidity, mortality and health care costs result from acute exacerbations, which are only partially responsive to current therapies. New approaches to treatment are needed. Most exacerbations are associated with rhinovirus infections, but mechanisms of exacerbation are poorly understood. We have reported that atopic asthmatics have increased susceptibility to rhinovirus infection and defective innate immune responses, with deficient rhinovirus-induction of IFN-beta and a novel family of IFNs-lambda1-3 in lower airway cells. Asthmatics also have increased colonisation with Chlamydophila pneumoniae (C.pn) and risk of invasive bacterial infections, C.pn reactivation is linked to asthma exacerbations, alpha/betaIFNs are required for immunity to C.pn, and we have shown LPS induction of IFN-lambda is deficient in asthma. Therefore, IFN deficiency seems an important novel mechanism of increased susceptibility to viral and bacterial infections, which both contribute to asthma exacerbations. Mechanisms of alpha/beta/lambdaIFN deficiency in asthma are unknown ?we seek to understand the mechanisms of deficient IFN production in asthma to identify specific targets for development of new therapies. We need to know whether these deficiencies are asthma/atopy-specific, whether they occur in children and if so, whether they are present at birth or acquired during childhood. We also need to discover if defects are observed in less invasive samples (PBMCs/serum). We hypothesise that IFN deficiency in asthma results from impaired expression/activation of key signalling molecules (from pathogen sensors to transcription factors) required for induction of alpha/beta/lambdaIFNs in response to viral & bacterial infection; that it is a specific feature of asthma (not atopy); it affects cells outside the respiratory tract as well as airway cells and is acquired in the first 5 yrs of life in relation to low exposure to infections (0-3yrs). To investigate these hypotheses, we will study detailed molecular mechanisms of alpha/beta/lambdaIFN induction in response to viral and bacterial infections/stimuli, in primary bronchial epithelial cells, airway macrophages and PBMCs from adults with clearly defined asthma and/or atopy. We will study IFN responses in cells from cord blood and blood taken at 1, 3 & 5 yrs of age in a birth cohort study. IFN production will be related to asthma outcomes determined at 6yrs, and to respiratory infections ascertained in yrs 0-3, along with other relevant risk factors by multiple logistic regression. The proposed studies will identify novel targets for development of new therapies for asthma exacerbations and determine which populations with asthma would be most likely to benefit from new therapies.