Upper respiratory infections due to rhinovirus have been shown to be the most common cause of asthma exacerbations in adults and children over the age of 2. Allergic asthmatic subjects appear to be particularly susceptible to rhinovirus induced increases in bronchial hyperresponsiveness. To help elucidate the pathogenic mechanisms responsible for these associations, we propose to explore the molecular mechanisms by which allergic inflammation enhances rhinovirus stimulated transcription of chemotactic cytokine (chemokine) genes in the airway epithelium. The underlying hypothesis for these studies is that persistent allergic inflammation of the airway enhances the epithelial response to rhinovirus infection, with increased synthesis of chemokines, recruitment and activation of lymphocytes and leukocytes, and ultimately increased bronchial hyperresponsiveness. We propose to first elucidate the impact of allergic inflammation on in vivo chemokine synthesis and viral load in the upper and lower airways following experimental rhinovirus infection using a comprehensive and quantitative approach. We will assess the consequences of rhinovirus infection on chemokine synthesis in the upper and lower airway; as well as whether the clinical status of the subject correlates with viral load.
The second aim i s to analyze the impact of pre-incubating primary airway epithelial cells with inflammatory stimuli on rhinovirus stimulated chemokine transcription in vitro. The ability of these primed epithelial cells to synthesize chemokines in response to subsequent rhinovirus infection will be assessed. Since apoptosis may serve to limit the inflammatory consequences of cell injury, we will also analyze the impact of epithelial cell priming on rhinovirus induced apoptosis.
The third aim i s to analyze the intracellular mechanisms regulating inflammatory gene transcription in airway epithelial cells following rhinovirus infection. We will analyze the molecular relationship between rhinovirus entry into a cell, viral replication, and chemokine transcription at the single cell level, and assess rhinovirus mediated transcription factor activation in vitro and in vivo. At the conclusion of this study, we expect to have a detailed molecular understanding of the effects of rhinovirus infection on airway epithelial cells as well as the factors that regulate these effects. We will also definitively analyze whether rhinovirus infects the lower airway, and correlate the effects of rhinovirus on chemokine synthesis in both the upper and lower airways with changes in bronchial hyperresponsiveness. These results will provide a necessary foundation for additional investigations into downstream inflammatory consequences of rhinovirus infection as well as potential targets for new intervention strategies.
| Eddleston, Jane; Christiansen, Sandra C; Jenkins, Gavin R et al. (2003) Bradykinin increases the in vivo expression of the CXC chemokine receptors CXCR1 and CXCR2 in patients with allergic rhinitis. J Allergy Clin Immunol 111:106-12 |
| Christiansen, Sandra C; Eddleston, Jane; Woessner, Katharine M et al. (2002) Up-regulation of functional kinin B1 receptors in allergic airway inflammation. J Immunol 169:2054-60 |
| Eddleston, Jane; Christiansen, Sandra C; Zuraw, Bruce L (2002) Functional expression of the C-X-C chemokine receptor CXCR4 by human bronchial epithelial cells: regulation by proinflammatory mediators. J Immunol 169:6445-51 |
