The human pathogen respiratory syncytial virus (RSV) induces mucosal inflammation by replication in the airway epithelium. In particular, severe lower respiratory tract infection (pneumonia and bronchiolitis) with RSV produces inflammatory mononuclear cell recruitment, airways remodeling and post-infectious airway hyper-reactivity (asthma). We and others have shown that RSV replication is a potent inducer of CC- and CXC-type chemokine synthesis, chemokines that play an important role in the subsequent immune response. Here we will comprehensively pursue our observations that lower respiratory tract cells produce greater amounts of eosinophilic CC chemokines than do upper respiratory tract cells. We hypothesize that the pathogenesis of RSV-induced respiratory tract inflammation is partly due to the consequence of cell type- dependent effects on inducible gene expression where lower respiratory tract cells express a different profile of inflammatory genes.
Three aims pursued in this project are: (1) we will apply cDNA microarrays to profile the pattern of inflammatory gene expression in RSV-infected lower airway epithelial cells. From this, we will establish a database of constitutive and RSV-inducible immune response genes. We will identify those genes whose expression is activated directly by virus or indirectly (through paracrine factors); (2) we will compare the patterns of RSV-inducible genes in tracheal and upper airway epithelial cells with that of lower respiratory tract cells to establish whether there are distinct patterns of inducible gene expression; and (3) we will identify genes induced following infection with clinical RSV isolates of the two major groups (A and B) associated with mild or severe disease to determine whether there are strain-dependent effects of RSV on epithelial gene expression. This multidisciplinary approach uses specific expertise in molecular biology, immunology and computational biology to systematically characterize the expression of inflammatory gene networks in RSV-infected epithelial cells. These studies are aimed at advancing our understanding of pathogen-induced mucosal inflammation and identifying gene targets whose activity can be modulated by therapeutic agents.
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