Cytokine Dysregulation, Virus Infections, And Asthma

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Abnormalities in immune response to viral infections and the virulence patterns of certain respiratory viruses have been felt to contribute significantly to the inception, progression, and severity of childhood asthma through unknown mechanisms. Using a birth cohort to study these relationships, we have made a number of novel and important observations pertaining to immune response profiles and virus infections during early life, and more recently with continued maturation of the cohort, we have placed these findings in the context of gene-environment interactions, developmental aspects, and gender differences. The most novel finding thus far has been that moderate to severe rhinovirus (RV)-induced wheezing illnesses during infancy are the most significant event in early life that predicts the subsequent development of childhood asthma. Moreover, these outcomes appear to be related to deficiencies in the production of interferons in response to these infections. Thus, the overall hypothesis of this project is that susceptibility to, and the clinical severity and manifestations of RV infections throughout childhood and early adolescence, is related to a deficiency in interferon responses to viral infection. We therefore propose to continue evaluation of cytokine response profiles from three tissue compartments (blood, nasal aspirates, and induced sputum) that have been previously stored and prospectively obtained as they relate to the development and physiological consequences of wheezing illnesses with specific viral pathogens, the development of various atopic phenotypes, and the expression and remission of asthma through infancy, childhood and early adolescence. This project comprises the entire COAST cohort that, in addition to its own specific aims and objectives, provides all of the phenotypic characterization and biologic specimens and DMA for the remaining projects in this application. Defining mechanisms by which viral infections impact on the clinical expression of childhood asthma is clearly relevant to the development of therapies aimed at both acute treatment in the form of medications and primary prevention in the form of vaccines.