Respiratory Syncytial Virus (RSV) is the leading cause of bronchiolitis in infants worldwide with healthcare costs estimated at $365-$585 million per year. Human epidemiological studies have identified age at initial infection as an independent risk factor for the development of childhood asthma. We have previously demonstrated in a mouse model that age of initial infection with RSV influences respiratory function in later life - infection of neonatal mice, d 7d of age, primes for a Th2 immune response that contributes to the development of long-term airways dysfunction. The mechanism(s) underlying the influence of age on the immune and pulmonary responses elicited in response to RSV infection remains obscure. Our preliminary data reveal that expression of IL-4Ra is developmentally regulated such that its expression declines on lung mDCs and Th1 cells as animals age (i.e. expression is highest in the neonate). Furthermore, downregulation of IL-4Ra expression during RSV infection in the neonate 1) inhibits the initial Th2 biased immune response and 2) protects against persistent Th2 immune deviation and pulmonary pathophysiology observed with secondary RSV infection in the adult. Our data support the expression of IL-4Ra in early life as a critical and novel age-dependent mechanism of severe RSV infection. Therefore, our hypothesis is that developmentally regulated expression of IL-4Ra on neonatal myeloid dendritic cells (mDCs) is responsible for biasing immune and pulmonary responses towards asthmatic type responses in later life. Specifically, our preliminary data suggest a unique mechanism whereby elevated levels of IL-4Ra on neonatal mDCs initiates a Th2-polarized immune response to RSV and signaling through IL-4Ra on neonatal Th1 cells results in their ablation. We will explore the validity of this hypothesis in the following specific aims:
Aim 1 will determine if age-related expression of IL-4Ra on mDCs is responsible for altered mDC function in neonatal RSV infection resulting in an asthma-promoting DC. We will leverage conditional cell ablation and adoptive transfer strategies to determine the functional role of IL-4Ra on neonatal mDCs.
Aim 2 will explore our prediction that elevated levels of IL-4Ra on neonatal Th1 cells are responsible for their specific ablation during neonatal RSV infection and for the persistence of the asthma phenotype following neonatal RSV infection.
Aim 3 will demonstrate that exacerbation of allergic asthma in adult mice is due to an altered Th2- inducing mDC formed during neonatal RSV infection. The concepts presented here are novel;and the data derived from these studies are expected to have a positive paradigm-shifting impact in understanding RSV- mediated asthma.
RSV causes significant morbidity and mortality in infants with a global disease burden of 64 million cases and 160,000 deaths annually. Our hypothesis is that a novel age-related mechanism mediated by elevated levels of IL-4Ra in early life, exists and programs for severe RSV, asthma, and susceptibility to asthma following neonatal RSV infection. If our hypothesis is correct, the concepts established here will not only have important implications for understanding mechanisms of RSV-mediated airway disease but also for understanding neonatal immunity and mechanisms of immunomodulation relevant to the development of safer and more effective pediatric vaccines.
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