Respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory tract disease in childhood. Severe RSV-induced disease is associated with childhood asthma, and the incidence of asthma in industrialized countries is increasing. Therefore, understanding the molecular and cellular correlates of RSV-and allergen-induced airway dysfunction is important for devising preventive vaccine and immunotherapeutic strategies to influence the pathogenesis of childhood asthma. The objective of this proposal is to define the virologic and immunologic determinants of airway hyperresponsiveness (AHR) induced by RSV infection in the setting of allergen sensitization. In particular, the mechanism of RSV G glycoprotein-induced airway dysfunction will e defined. In addition, the role of selected cytokines and T cell subsets on the induction of AHR in ovalbumin (ova)-sensitized, RSV-infected mice will be defined. Under normal conditions RSV infection induces a Th1- like pattern of cytokine expression. Our preliminary data supports the hypothesis that ova-sensitization produces an immunologic environment that promotes RSV-specific CD4+ Th2 responses to infection which further potentiate ova-specific allergic airway inflammation and AHR. Further, we hypothesize that RSV infection can permanently alter the immune response to aeroallergens through T cell production of factors such as IFN-alpha or IL-15 that influence memory induction in ova-specific """"""""bystander"""""""" T lymphocytes. To test this hypotheses, we will use well characterized murine models of RSV infection and ova sensitization, and measure methacholine-induced AHR in anesthetized, mechanically- ventilated mice by whole body plethysmography. In addition to defining the role of RSV- and ova-induced cytokines and T lymphocytes subsets in mediating protection from or enhancement of AHR, candidate vaccines and immunotherapeutic approaches will be evaluated for their ability to reduce AHR in ova-sensitized mice following RSV challenge.
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