The long-term goal of this project is to understand how viral respiratory infections lead to asthma. In that context, the application proposes that airway epithelial cells (the viral host cells) provide critical biochemical signals for immune-cell influx and activation, and that this epithelial-immune cell interaction is a critical feature of airway inflammation and hyperreactivity. The current project is based on new findings related to epithelial expression of a critical immune modulator, the beta-chemokine designated RANTES. In particular, studies of isolated human airway epithelial cells indicate that polarized secretion of RANTES is required to direct immune cell traffic. Expression of the RANTES gene, in contrast to other epithelial immune-response genes, appears to be directly and markedly induced by infection with respiratory syncytial virus (RSV) or Sendai virus (SdV), and induction by virus or interferon-gamma (IFN- gamma) appears to be mediated by a marked increase in mRNA stability in the setting of a relatively low rate of gene transcription. The application proposes that the distinct behavior of RANTES gene expression reflects a selective dependence on this post-transcriptional mechanism. Preliminary studies indicate that basal instability of RANTES mRNA is mediated at least in part by a distinct cis-acting mRNA turnover element in the 3'-UTR of the RANTES gene, and this (or other) specific elements may be the target for induction by virus. The findings also raise the possibility that increased airway levels of RANTES during RSV infection in human subjects reflects an increase in epithelial production. The application proposes that overexpression of epithelial RANTES may provide an advantage for limiting infection in normal hosts but a disadvantage for subjects with asthma. Thus, in normal hosts, the infected cell may take advantage of the viral machinery to ensure early expression of RANTES and consequent immune defense. However, the potent effects of RANTES on chemotaxis and activation of T cells and other immune cells may also underlie the selective association of RSV infection with asthma exacerbation in infants. In fact, an inherited or acquired propensity for overexpression of the RANTES gene may underlie a relationship of RSV infection to ongoing asthma even later in life.
The specific aims are: 1) Define the post-transcriptional mechanism for virus-inducible expression of the RANTES gene in airway epithelial cells; and 2) Define the role and the mechanism of regulation for RANTES gene expression in a mouse model of viral infection and airway hyperreactivity.
