Prevention of severe RSV infection by a helminth-induced serum factor that elicits antiviral monocytes?

In babies and toddlers worldwide, respiratory syncytial virus (RSV) is the most common cause of a type of chest infection called bronchiolitis and causes severe lung inflammation. 2-3% 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. 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 prophylactic antibody against 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 previously reported that infection with a gut parasite worm can reduce the number of viral particles in the lungs and disease severity in a mouse model of RSV infection. More recently, we have found that protection from severe RSV infection in this model is associated with increased production of immune cells called monocytes in the bone marrow and their accumulation in the lung. Monocytes are thought to be important in the immune response to RSV, but how they exert their antiviral effect is not fully understood. Importantly, all the above effects of parasite infection can be recapitulated with cell-free blood serum from infected mice, unless it has been heated. This suggests a central role for a protein in the serum, such as an immune system messenger molecule, as the soluble RSV-protective factor. If we can identify this factor, and work out what it is doing, we may in the future be able to develop a novel approach to protection from severe RSV disease in young children.

Here, we will initially use our mouse model to study which subgroups of monocytes occur and which monocyte genes are 'switched on' during parasite infection, in order to define the mechanisms by which monocytes limit RSV infection. We will then use two approaches to identify the RSV-protective factor from blood serum; one where we measure, block and replace known candidate immune mediators in the serum, and another where we test groups of serum proteins of different sizes for their anti-RSV effect, followed by measurement of the proteins within the effective group and identification of candidate factors. These will then be tested individually for their antiviral effect and the RSV-protective factor will be identified. Finally, to translate our findings from the mouse model to humans, we will use existing blood samples from Ugandan children with and without gut parasite worms. We will assess the activation of genes to see if those with parasite infection also have more monocytes and more active anti-viral genes in their blood and we will measure the concentration of the newly identified RSV-protective factor to see if it is elevated in parasite-infected children.

These studies will let us find out which parasite-induced factor is responsible for the protection from RSV infection and how monocytes contribute to this protection. They will also tell us if the RSV-protective factor and/or monocytes will be promising new targets to develop preventive treatment for severe RSV bronchiolitis.

Respiratory syncytial virus (RSV), the main cause of viral bronchiolitis, results in hospitalisation of 2-3% of all infants and can cause life-threatening disease. With significant morbidity, RSV bronchiolitis has major health and economic implications, but specific therapy and, for most infants, affordable prevention is lacking.
We previously reported that RSV titres are reduced and disease is prevented in RSV-infected mice co-infected with the gut nematode Heligmosomoides polygyrus (Hp). Our recent preliminary data suggest that Hp infection induces monopoiesis and lung monocytosis and that monocyte depletion during Hp infection ablates its anti-RSV effect. Both lung monocytosis and the RSV-protection were transferred by non-heated serum of Hp infected mice, suggesting a RSV-protective protein factor in serum, e.g. a cytokine.
Here, we will test the hypothesis that Hp infection, through serum mediators, drives monopoiesis and recruitment of monocytes to the lung, which prime the lung's antiviral response, conferring protection from severe RSV infection. We will use flow cytometry, single cell and bulk RNAseq and genetically modified strains in mouse models to determine if Hp induces transcriptionally distinct monocyte populations with anti-RSV effects, and to define their kinetics. To translate murine findings, we will use RNAseq of existing blood samples from Ugandan children with/without gut helminth infection to determine if helminths also induce monocytosis and antiviral gene expression in humans. In parallel, we will use both a candidate cytokine and an open proteomics approach to identify the RSV-protective serum factor, which will be validated by quantification in serum from children with/without gut helminth infection.
These translational studies will define the antiviral roles of Hp-induced monocytes in RSV infection, discover the RSV-protective serum factor and may identify these as new targets for the prevention of 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, especially those mechanisms which act on mononuclear phagocytes and those used by these cells to mediate antiviral immunity in the respiratory tract induced by intestinal helminths, linking 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. This project will raise novel questions, which will be the basis for Honours undergraduate and MSc projects we will offer to engender interest in our field of research. Time frame: 1-5 years

This project will give Dr Matthew Burgess, a post-doctoral scientist employed for this project, training and learning opportunities in research management, scientific writing and presenting, public presenting to lay audiences and in commercialisation considerations. While all of these are generic skills, which will be useful in careers in science and beyond, they will prepare Dr Burgess for a successful fellowship application and a career as an independent researcher, which he aims for. 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 of infants and in 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, inparticular once we have identified the helminth-induced serum factor, these will likely 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. Such widely available prevention, which is currently lacking, may in the future 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.