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

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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.