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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI040685-03
Application #
2837478
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Adams, Ken
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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