Regulation of interferon production in the lung during respiratory syncytial virus infection

All children are infected with respiratory syncytial virus (RSV) before age of two and most of the time the infection gives symptoms of a normal cold. However, in 2-3% of infants RSV infection lead to severe disease, called bronchiolitis, and to hospitalisation. Bronchiolitis is inflammation of the lower parts of the lungs, the bronchioles. During RSV infection the immune system has to combat the virus but also make sure that the lungs are not damaged and this appears to fail in the small % of infants who develop bronchiolitis. Therefore, it is important to understand how the immune responses are induced and regulated during RSV infection. This research proposal will focus on how the immune system senses the presence of RSV in the lungs and how this lead to production of early mediators, called interferons, which have been implicated both in resistance to the virus and in prevention of bronchiolitis. The results from this proposal may therefore impact on strategies for finding efficient immune therapies for bronchiolitis or for developing vaccines against RSV.

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in humans. In 2-3% of children the infection leads to severe bronchiolitis such that RSV is by far the most common cause of hospitalisation among infants. Severe bronchiolitis is associated with polymorphisms in several innate immune response genes, in particular many that control the IFN system. Innate IFNs (type I and III) are produced very early and upon direct recognition of the virus. They are important for inducing antiviral responses and to activate cells of the innate and adaptive immune systems. The role of these cytokines in regulating host resistance and immunopathology during RSV infection in young and adults is poorly understood.
Using a mouse model of RSV disease I will study the molecular and cellular regulation of innate IFN production in response to RSV in vivo. Firstly, I will elucidate which cells are infected by RSV and which cells produce IFNs in response to RSV in vivo. In addition, I will determine which pattern recognition receptors are involved in the induction of innate IFN production. Secondly, I will test the hypothesis that the production of innate IFNs might be limited in the young and that this contributes to the development of immunopathology (bronchiolitis). Neonatal and adult mice lacking individual IFN receptors will be infected with RSV and development of immunopathology will be compared. This will test the prediction that neonates are more dependent on signalling via each of the IFN receptors than adults because of lower overall IFN production. The results from this proposal will increase our understanding of the role of IFNs in immune responses to RSV and in the development of immunopathology during RSV infection. This will assist the development of strategies to find an efficient immune therapy to prevent RSV-associated bronchiolitis and to develop vaccines against RSV.