The overall goal of this application is to determine how specific genetic, biologic, and immunologic characteristics interact to predispose individuals to develop asthma. In that context, over the last three years, we have developed a carefully selected cohort of 206 infants with respiratory syncytial virus (RSV) bronchiolitis (the RBEL (RSV Bronchiolitis in Early Life) cohort) who are at substantial risk of developing asthma. Surprisingly, physicians have already diagnosed asthma in 40 percent of the children in the RBEL cohort. The children have had at least one year of follow-up. This project builds upon our previous work establishing the largest prospective U.S. study children with RSV bronchiolitis severe enough to require hospitalization and proposes that this study should be continued for an additional five years in order to more definitively establish the diagnosis of asthma in this cohort. The interaction of RSV with the host epithelial-immune system and underlying genetic background is unclear. Accordingly, Aim I proposes to evaluate the association between genotypes associated with atopy, the IL-4 receptor a and IL- 13 single nucleotide polymorphisms, and the development of an asthmatic phenotype in the RBEL cohort of children. Given the appropriate risk factors, RSV elicits an immune response characterized by inflammatory cell influx, especially T cells, into the airway. Accordingly, Aim II proposes to evaluate the effect of airway epithelial inflammation, demonstrated by persistent RANTES (Regulated upon Activation, Normal T-cell Expressed) expression in airway epithelial cells, on the development of an asthmatic phenotype in the RBEL cohort of children. This possibility is supported by evidence of increased RANTES expression (by mRNA stabilization) in human tracheal epithelial cells infected with RSV in vitro and in upper airway epithelial cells from RBEL infants with RSV bronchiolitis. The T cell immune response following viral infection appears to be primarily Th1-type; however, in the setting of RSV infection, there actually may be a skewing of the immune response to a Th2 phenotype early in life. Accordingly, Aim III proposes to evaluate prospectively the T cell profile, Th1 vs. Th2 phenotype, as defined by cytokine expression and other phenotypic markers, in the RBEL cohort of children who are at risk of developing an asthmatic phenotype. Therefore, this application will lead to a better understanding of the interaction of genetic, biologic, and immunologic factors following serious RSV infection which lead to the development of asthma in early life. Furthermore, we propose to develop an asthma predictive index for children with serious RSV infection based upon the findings of the studies outlined in this application. Such an index would be extremely valuable to clinicians taking care of children following a severe RSV infection to provide prognostic information and to identify children at highest risk for the development of asthma who may benefit from an early intervention or treatment.
