Asthma exacerbates during respiratory infection, which may contribute to its maintenance and progression. Current therapies fail to reverse this process, and development of asthma cannot be prevented with current interventions in the absence of clear delineation of the etiology. However, most asthma patients can trace the origin of their disease, the early onset of wheezing, to the first 2-3 years of life. Wheezing may develop earlier after an episode of bronchiolitis, caused by infection of the lower respiratory tract with respiratory syncytial virus (RSV). RSV bronchiolitis occurs mostly during the first few months of life, when the newborn's immune system is still immature, TH2-biased and lacks prior experience to the virus. Apparently, this neonatal deficiency can be compensated for by maternally derived factors. This project focuses on antenatal to early postnatal factors derived from the state of maternal immunity that may determine the outcome of neonatal RSV infection in the offspring. The proposed studies will be conducted in a mouse model, which has been validated to reveal the influences of maternal immunity on the response of the neonate to RSV infection.
The specific aims are: 1- To define the influence of maternal immunity in the response of the newborn to neonatal RSV infection. Studies are designed to delineate those aspects of the neonatal response(s) to identify which component of the response is influenced by maternal immunity from allergic and non-allergic, and RSV-immune and non-immune mothers. 2- To elucidate the underlying mechanisms whereby maternal immunity influences the response of the newborn to RSV infection. Studies will determine how the influence of maternal immunity is mediated and how it contributes to shaping the response of the newborn to RSV infection. 3- To determine if maternal immunity influences the response of the newborn to allergen exposure following neonatal RSV infection. RSV infection enhances allergen-mediated airway dysfunction. Studies will determine if and how maternal immunity, by influencing the response to RSV in the newborn, may modulate the response to subsequent allergen exposure. This project will define a critical and potentially malleable link between maternal immunity and the risk of development of RSV bronchiolitis and associated long-term sequelae in the offspring. In the long-term, this project will improve our understanding of the role of infection in asthma. Understanding when and how these infections contribute to the pathogenesis of asthma and allergic airway disease is prerequisite to the development of effective therapies to prevent or cure the disease.
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