Viral infections such as RSV are an important precipitant of childhood asthma. The overall objective of this grant proposal is therefore to understand the mechanism by which Respiratory Syncytial Virus (RSV) induces eosinophilic airway inflammation in atopic mice and to subsequently test the hypothesis that DNA immunization can inhibit RSV induced airway inflammation. In the first series of experiments we will demonstrate that viral infections such as RSV which are a frequent precipitant of childhood asthma induce eosinophilic inflammation in atopic mice by inducing the expression of IL-5 by CD8 + T cells and C chemokines by airway epithelium. The importance of the expression of these CC chemokines to eosinophil recruitment will be assessed in vivo in a mouse model of RSV infection of atopic mice pretreated with Ab to CC chemokines. To explore the possibility that a deficiency in functional CpG sequences in RSV promotes Th2 responses, we will infect mice with either RSV (? CpG suppressed), RSV and CpG, or Adenovirus (not CpG suppressed) to assess Th1 versus Th2 responses, eosinophilic airway inflammation and bronchial hyperreactivity. Additional experiments will determine which DNA based vaccine strategy (ISS alone, DNA-RSV-F alone, or the sequential combination) is the most effective in inhibiting eosinophilic inflammation, airway hyperreactivity and viral load in atopic mice challenged with RSV. To explore the mechanism of action of ISS in vivo, we will either use neutralizing Abs to individual cytokines (IL-12 and IFNs derived from NK cell and monocyte/macrophages) or neutralizing Ab to deplete NK cells to define the relative importance of either individual cytokines or NK cells to the mechanism of action of ISS in vivo. Overall these studies will contribute to our understanding of the mechanism of eosinophilic inflammation during RSV infection and suggest candidate vaccine strategies to inhibit RSV infection and airway inflammation.
| Broide, D; Cho, J Y; Miller, M et al. (2000) Modulation of asthmatic response by immunostimulatory DNA sequences. Springer Semin Immunopathol 22:117-24 |
