Recent observations have indicated that asthma developing in the first decade of life may have its inception during infancy. Both genetic/host (atopy) and environmental (allergens, viruses) factors have been implicated in asthma pathogenesis, but their relative importance either alone, or in combination, has yet to be established. To study the contribution of, and the interactions among age (development), patterns of cytokine secretion, and virus infections on the subsequent development of asthma, a relevant animal model has been developed. Sendai (parainfluenza 1) virus infections in an atopic strain of rats (Brown Norway [BN]) lead to the development of lung inflammation and altered physiology that parallel similar findings in human asthma. The development of this asthma-like phenotype appears to be related to differences in cytokine response patterns (attenuated Th1 type responses) following infection; moreover, the development of the phenotype can be prevented in the BN strain if these animals are treated with IFN-gamma at the time of infection. Accumulated data both in vitro and in vivo indicate that the development of these abnormalities is potentially related to two important aspects of the immune response to the virus infection. First, abnormalities in the innate immune response (decreased NK cell production of IFN-gamma to the virus) which appears to be operative only during a critical time period in the development of the rat (weanling versus adult); and second, abnormalities in the resolution of the immunoinflammatory response to the infection with the BN strain shifting to a prolonged, ongoing Th2 cytokine response within the airway. Finally, as a consequence of these earlier events, additional data indicate that once the asthmatic phenotype develops, the airway is rendered vulnerable to insult from other exogenous stimuli (allergen exposure). Using this well developed animal model of virus-induced airway dysfunction that incorporates genetic (cytokine imbalance or dysregulation), environmental (virus infection), and developmental (age) components, this project aims to comprehensively analyze and define immunologic and biologic mechanisms that are responsible for similar developments during infancy and childhood in their human counterpart.
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