Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and lower respiratory tract infection in infants. Acute RSV leads to wheezing, and re-infection, a common event, results in even more severe airway symptoms. The pathogenic basis for the association between RSV and reactive airway disease and the subsequent development of asthma is not clearly elucidated. Nonetheless, RSV bronchiolitis in infancy appears associated with an increased risk for later development of asthma, a risk that may persist for several years. We have demonstrated in a murine model that prior RSV infection enhances the airway response (airway inflammation and hyperresponsiveness) to subsequent allergen exposure. Our hypothesis is that the age at initial RSV infection not only plays an important role in response to the acute infection, but also dictates or shapes the response to subsequent re-infection with RSV or allergen exposure. Both the immune/inflammatory responses and neurogenic control of airway function are age-dependent. We now know that the younger the age at initial encounter with RSV, the more vigorous the inflammatory response and airway responsiveness are, both acutely and subsequently on re-infection or allergen-exposure. Using a model of RSV infection/re-infection/allergen exposure, we will further characterize the immune/inflammatory responses and airway function following RSV infection in < 1, 3 and 8 week old mice. In these responses, we will systematically define the role of RSV structural proteins, cytokine production, neuropeptide levels, the production of RSV-specific antibody, especially IgE, and identify, at the T cell level, how acute RSV at the different ages influences the differentiation of T helper cells. Based on this information, we will then define how these factors direct the subsequent response to re-infection or allergen. The approach proposed is supported by extensive preliminary data, the availability of all of the molecular and cellular techniques, reagents and mutant strains of mice, as well as the ability to monitor infection and lung function in mice less than 1 week of age. The information generated from these studies will delineate the important age-dependent influences on the immune/inflammatory response in the lung and reveal new options for therapeutic intervention to prevent the long-term sequelae of RSV infection in infancy.
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