Mechanisms of helminth induced antiviral immunity to RSV infection

In babies and toddlers worldwide, respiratory syncytial virus (RSV) is the most common cause of a type of chest infections called bronchiolitis and causes a severe lung inflammation. 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. This happens particularly when very high numbers of virus particles are present after infection. Death due to RSV is rare in the UK, but it is a significant problem in developing countries. 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. Despite all of this, no specific treatment or effective, widely available preventative interventions exist and novel approaches are urgently required. Palivizumab, a monoclonal antibody to RSV can prevent hospital admissions by about 50%, but due to high cost its use is limited to small groups of high risk infants in affluent countries.
We have recently found that infection with a gut parasite worm can reduce the number of viral particles in the lungs in a mouse model of RSV infection and block the accumulation of the immune system cells that drive inflammation. In worm-infected mice, we also found an increased expression of antiviral genes that are involved in containing and eliminating the virus. These observations suggest that a worm infection of the gut can lead to an antiviral state in the lung which reduces numbers of viral particles, immune cell responses, inflammation, and disease severity in RSV infection.
Here, we will initially use our mouse model to study which cells and/or substances of the mouse's immune system are responsible for the antiviral effects during parasite worm infection and whether these cells and/or substances can be used instead of worm infection to reduce the severity of RSV infection. We will also use this model to test whether worm-derived products alone, rather than the full process of worm infection, are sufficient for the desired antiviral effects. To find out if gut parasite worm infections also lead to antiviral effects against RSV in humans we will study children in Uganda where these worm infections are still common. We will take small samples from the inner lining of the nose, where RSV initially grows, and blood samples to compare the levels of antiviral genes (with and without RSV exposure in the laboratory) between children with and without gut worm infection.
These studies will let us find out which immune cells or substances that arise during worm infection, lead to an antiviral state in the lung and whether these substances or cells will be promising new targets to develop preventive treatment for severe RSV bronchiolitis.

RSV is the main cause of viral bronchiolitis in infants worldwide. It results in hospitalisation of 2% of all infants and, particularly in those with a high viral load at the onset, may cause severe life threatening disease. With significant morbidity and, in developing countries, mortality, RSV bronchiolitis has major health and economic implications. Despite this, only supportive therapy is available and effective and affordable prevention is lacking. The costly use of palivizumab in prevention is limited to small groups of high risk infants in affluent settings.
Using a mouse model, we have recently found that viral titres and immune/inflammatory cell responses following RSV infection were significantly reduced in mice previously infected with the strictly enteric nematode Heligmosomoides polygyrus (Hp). This was associated with increased expression of the antiviral genes interferon-beta, viperin and OAS in the lungs of Hp infected mice.
We will test the hypothesis that immune mediators/cells induced by gut helminth infection enhance lung antiviral immune responses, thus reducing viral load, lung inflammation, and disease in RSV infection. We will use mouse models to determine if the Hp induced antiviral effects require adaptive immunity and Hp infection with associated tissue damage, or if they can be triggered by Hp products alone. We will then define which innate immune mediators/pathways are required for the Hp antiviral effect and test if these can reduce the severity of RSV infection in the absence of Hp infection. In a parallel clinical study, we will compare Ugandan children with and without gut helminth infection to determine if this also enhances antiviral responses in the human respiratory tract.
These translational studies will define the immune mediators/cells responsible for helminth induced enhanced antiviral lung responses and may identify these as new targets for the prevention of severe RSV disease.

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 by which helminths induce antiviral immunity in the respiratory tract and which link gut and lung immunity. Our work will stimulate further research into mechanisms and triggers of helminth induced antiviral immunity to other respiratory 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, virology, parasitology, 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 prevent, 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 prevention/treatment/drug targets and biomarkers predicting immunity to respiratory viruses. Time frame: 5-10 years.
In the longer run, we expect that our work will provide the basis for the development of effective and widely available prevention (and possibly also treatment) of severe disease not only in viral bronchiolitis and pneumonia but also for virus induced asthma exacerbation in children and adults. Once available, such prevention, which is curently lacking, may prevent severe viral bronchiolitis, or reduce its severity by reducing viral load, and may also allow effective prevention/ early treatment of virus induced asthma exacerbations. Such advances would considerably improve the wellbeing and quality of life of children and adults at risk of 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.