Rhinovirus (RV) infections are the single most common trigger of exacerbations of asthma in children and continue to contribute to asthma-related morbidity in adults, but little is known of the mechanisms by which RV produces lower airway dysfunction. Based on evidence implicating the eosinophil as a principal effector cell in asthma, and preliminary data, the following hypothesis is proposed: RV-induced immune responses that enhance the recruitment and activation of eosinophils in the lower airway are a major factor in the pathogenesis of virus-induced exacerbations of asthma. The following specific aims will establish mechanisms by which eosinophils, T-cells, and epithelial cells interactively contribute to the pathogenesis of RV-induced exacerbations of asthma: 1) To establish the direct effects of RV on eosinophil activation in terms of survival, degranulation, and production of GM-CSF and superoxide; 2) To define paracrine effects of RV-induced cytokines from T-cells (IFN-g, GM-CSF, and IL-5), and epithelial cells (RANTES and GM-CSF) on eosinophil recruitment and function, and RV replication in epithelial cells; 3) To define the mechanisms by which eosinophils process complex viral antigens and present them to RV-specific T-cells, and determine the consequences of this process in terms of T-cell cytokine production, and subsequent """"""""feedback"""""""" activation of eosinophils; 4) To use recombinant RV proteins to define epitopes recognized by RV-specific T-cells, determine which immunogenic epitopes are conserved between serotypes, and establish whether these conserved epitopes induce Th1 or Th2-like cytokines; and 5) To validate the in vitro findings of Specific Aims 1-4 by using RT-PCR and ELISA to analyze nasal secretions and sputum from asthmatic versus normal children with naturally-occurring RV colds for anti-viral (e.g., IFNa) and pro-inflammatory cytokines (RANTES, GM-CSF, IL-5, TNFa). These studies will identify the key cells and mediators involved in the pathogenesis of RV-induced asthma exacerbations, enabling future studies of virus-mediated gene activation, and the subsequent development of new intervention strategies.
| Parry, D E; Busse, W W; Sukow, K A et al. (2000) Rhinovirus-induced PBMC responses and outcome of experimental infection in allergic subjects. J Allergy Clin Immunol 105:692-8 |
