Pro-inflammatory lung dendritic cells in stratified severe RSV bronchiolitis

BACKGROUND: Respiratory syncytial virus (RSV) is worldwide the most common cause of a type of chest infections in babies and toddlers called bronchiolitis, which can cause severe disease and occasionally death. Vaccination or specific treatment is not available. Due to treatment costs and costs for the wider society (e.g. days lost at work for parents/ carers) RSV is responsible for a major financial burden. 2% of all babies in the UK have to be admitted to hospital with RSV bronchiolitis and some of them develop very severe and sometimes life threatening disease which causes breathing to fail. These babies require breathing support where a machine inflates their lungs. This is usually only required for a few days, but in a third of these very severe cases the disease fails to improve quickly making longer machine breathing support necessary.

Breathing problems in RSV bronchiolitis are thought to be due to very severe inflammation of the small ends of the breathing tubes in the lung. The mechanisms that maintain this inflammation and delay improvement of disease are not well understood. Work in mouse models suggests that two types if immune cells have important roles in lung inflammation after RSV infection; one of these are called T cells and the other dendritic cells (DCs) which are the main activators of T cells.

PILOT DATA: In a pilot study of infants with RSV bronchiolitis who were on machine breathing support, we have recently detected substantial numbers of DCs and T cells in small lung washes. Lung washes of infants with healthy uninfected lungs do not contain these cells.

HYPOTHESIS AND PROJECT PLaN: We hypothesise that activated lung DCs and T cells which can lead to inflammation, are responsible for continuing inflammation and the delay in improvement of disease in babies with longer lasting severe RSV bronchiolitis. We will take small lung washes from babies with severe RSV disease who are on machine breathing support comparing those who only need this support briefly to those who require it for a longer time. In the lung washes we will count DCs and different groups of T cells, measure the activation of DCs and their ability to activate T cells and we will find out if signal substances in the wash fluid are able to cause the development and / or activation of DCs. We will then use the mouse model of RSV infection to prove or disprove that DCs are required to maintain inflammation by taking DCs out of the mouse and then replacing them.

OUTLOOK: If we find that activated lung DCs and associated T cells are responsible for maintaining inflammation and delaying improvement of disease in severe long lasting RSV bronchiolitis, these studies will identify lung DCs as a promising target for the development of new anti-inflammatory therapies for this condition. In addition numbers and properties of lung DC may also be useful as a marker to predict delayed resoltion of severe RSV disease.

RSV is the main cause of viral bronchiolitis in infants worldwide. With significant morbidity and mortality RSV bronchiolitis has major health and economic implications. It results in hospitalisation of 2% of all infants who may develop severe disease with respiratory failure requiring mechanical ventilation. While for most this is only required for a few days, in a third of very severe cases resolution of disease is delayed necessitating prolonged mechanical ventilation.

Respiratory disease in RSV bronchiolitis is due to airflow obstruction resulting from excessive inflammation of the small terminal airways. The immune mechanisms by which this inflammation is maintained, delaying resolution of disease, are not known. Mouse models of RSV infection suggest important roles of the expanded population of pro-inflammatory conventional dendritic cells (cDCs) and associated T cell responses. We have recently detected sizable populations of activated cDCs and T cells in bronchoalveolar lavages (BAL) from infants with severe RSV disease.

Here, we will test the hypothesis that activated lung cDCs and associated pro-inflammatory T cell responses are essential for the maintenance of airway inflammation in prolonged severe RSV bronchiolitis. Using a clinical study comparing infants with faster or delayed resolution of RSV disease, we will determine cDC numbers in BAL, their activation status and their ability to induce pro-inflammatory T cell responses, and we will assess cytokine concentrations in BAL fluid and their ability to differentiate and activate cDCs. Using the mouse model of RSV infection, we will define the role of cDCs for lung inflammation and disease by depletion and reconstitution.

These translational studies will define the role of cDCs and associated T cell responses for the maintenance of inflammation in delayed resolution of severe RSV bronchiolitis and may identify cDCs as a new treatment target and biomarker in this condition.

Our research and the knowledge gained will in the first instance have impact on the scientific community where it will contribute to the understanding of basic immune mechanisms of virus induced lung inflammation and will elucidate disease mechanisms of severe RSV bronchiolitis in infants. Our work will stimulate further research into mechanisms of pulmonary inflammation induced by other viruses not only in young children but also in other high risk groups including the elderly and people with asthma. This may recruit new scientists into this field of work, and will contribute to teaching and learning in the fields of immunology, inflammation, respiratory medicine and paediatrics. Time frame: 1-5 years
This project will give the post-doc employed training and learning opportunities in research management, scientific writing and presenting, public presenting to lay audiences and in commercialisation considerations. All of these are generic skills which will be useful in careers in science and beyond. Time frame: 1-5 years.
Our work may also have early impact on third sector organisations interested in supporting high impact research to improve the management and outcomes in severe respiratory viral disease in infants and childhood asthma (e.g. Asthma UK, British Lung Foundation, Action Medical Research, Wellcome Trust). These organisations may be interested in funding associated and follow-on projects and may be able to fundraise specifically for these using our ideas and results. Time frame: 1-5 years.
Once firm results are available they will hopefully be of interest to industry and provide an opportunity for further definition and validation of future treatment / drug targets and biomarkers. Time frame: 5-10 years.
In the longer run, we expect that our work will provide the basis for the development of effective treatment for virus induced lung inflammation not only for viral bronchiolitis and pneumonia but also for virus induced asthma exacerbation in children and adults. Once available such therapy, which is currently not available, may shorten the course of or even prevent severe viral bronchiolitis and may allow effective treatment of virus induced asthma exacerbations. Such advances would considerably improve the well being and quality of life of children and adults with severe respiratory viral infections and of those with asthma, reduce morbidity and probably mortality and provide substantial savings for health care systems around the world including in the NHS. Time frame: 10-15 years.