Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infection and hospitalization for airway obstruction in young children in the U.S. (about 90,000 admissions annually). While every child is """"""""susceptible"""""""" to RSV infection (will be infected by age 2 years), the developmental, environmental or genetic factors that predispose children for acute and chronic airway obstruction following RSV infection remain unclear. However, epidemiologic studies demonstrate a clear role for familial predisposition in RSV related disease (infants with a family history of atopy and asthma are more likely to develop bronchiolitis and require hospitalization). The reason why some individuals develop severe disease following RSV infection is unknown, but is likely to involve mechanisms that control the initial infection, viral replication and resolution of infection. Recent data demonstrate that strains of inbred mice vary in RSV susceptibility. This trait was transmitted to offspring, suggesting that factors controlling viral processing are inherited. The studies outlined in this grant application propose to use these mouse strains to further delineate the mode of inheritance and the mouse chromosomal regions that encode the major determinants of RSV susceptibility. The quantitative trait loci (QTL) identified in the mouse can then be used to identify candidate genes controlling RSV susceptibility, and by comparative mapping, candidate genes in the human. Therefore, this application tests the hypothesis that susceptibility to RSV infection is a complex genetic trait and the chromosomal regions containing major determinants for susceptibility to RSV can be identified and mapped, and candidate genes for RSV susceptibility can be identified. To test this hypothesis, three Specific Aims are proposed.
Aim 1 proposes to perform trait segregation analysis to estimate the number of genes involved in the RSV susceptibility phenotype, the mode of inheritance of these gene(s), and the potential effects of sex linkage and parental imprinting on the RSV susceptibility phenotype.
Aims 2 and 3 propose to identify chromosomal regions with linkage to RSV susceptibility by phenotyping and performing linkage analysis on Recombinant Inbred (RI) mouse strains (Aim 2) and by performing Quantitative Trait Locus (QTL) analysis of F2 and offspring derived from the F1 backcrossed with the susceptible AKR strain (Aim 3). The overall goal of the studies proposed is to estimate the number of genes associated with the RSV susceptibility/ resistance in genetically-defined inbred mouse strains, allowing us to focus on these regions for potential candidate genes regulating RSV responses. Future studies will focus on further characterization of the candidate genes located in the DNA segments identified in this grant application.
