The rhinovirus (RV) common cold often provokes wheezing in patients with asthma. Although the consequences of such infections are often substantial, the precise mechanism by which RV upper respiratory illnesses increase asthma have yet to be fully established. The overall objective of this proposal is to establish the links among RV infections and alterations in biologic and physiologic events which present clinically as asthma. To accomplish this goal, we developed an in vivo human model which allows assessment and correlation of airway physiology and biology during an experimental RV16 infection. Using this approach, we have established that intranasal inoculation with live RV16 of allergic subjects causes a significant increase in airway responsiveness and in probability for the development of a late allergic reaction to inhaled antigen. Based upon these observations, we hypothesize that a principal mechanism for RV- provoked asthma is viral activation of airway cells to secret pro- inflammatory cytokines, which amplify allergic bronchial inflammation by: (1) increasing the local expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), (2) promoting greater recruitment of inflammatory cells, and (3) by directly potentiating inflammatory cell function. Furthermore, we propose that RV infects cells in the lower airways to cause these changes in the lung, and thus leads to a more persistent increase in bronchial inflammation and responsiveness after the acute illness. To confirm these hypotheses and thereby establish mechanisms for RV-provoked asthma, patients with allergic rhinitis and asthma will be given an experimental intranasal RV16 infection and then undergo bronchoscopy, segmental bronchoprovocation with antigen, lavage and biopsy. Using this approach, the effect of RV16 illness on selected cytokine mRNA will be determined by solution and in situ hybridization; further, bronchoalveolar lavage fluid, obtained immediately and 48 hrs after segmental antigen challenge, will be analyzed by ELISA techniques for cytokines. The effect of RV16 illness on ICAM-1 expression will be determined by flow cytometry of airway eosinophils, lymphocytes, and epithelial cells, quantitation of soluble ICAM-1 in lavage fluid, and in situ hybridization of biopsy tissue and lavage cells. Finally, nasal and bronchial fluid, cells, and tissues will be evaluated for RV16 infection by culture and in situ hybridization with an RV16 oligonucleotide probe. These findings will be correlated with concomitant changes in airway inflammatory mediator release, cellular components of inflammation, and pulmonary physiology. From these experiments we will understand and establish, more specifically, the immunobiology of the airway response to RV and mechanisms of virus-induced bronchial inflammation, hyperresponsiveness, and asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026609-07
Application #
2063444
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-09-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Gern, J E; Busse, W W (1999) Association of rhinovirus infections with asthma. Clin Microbiol Rev 12:9-18
Varner, A E; Busse, W W; Lemanske Jr, R F (1998) Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol 81:347-51
Handzel, Z T; Busse, W W; Sedgwick, J B et al. (1998) Eosinophils bind rhinovirus and activate virus-specific T cells. J Immunol 160:1279-84
Folkerts, G; Busse, W W; Nijkamp, F P et al. (1998) Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 157:1708-20
Gern, J E; Dick, E C; Kelly, E A et al. (1997) Rhinovirus-specific T cells recognize both shared and serotype-restricted viral epitopes. J Infect Dis 175:1108-14
Jarjour, N N; Sedgwick, J B; Swensen, C A et al. (1997) Late allergic airway response to segmental bronchopulmonary provocation in allergic subjects is related to peripheral blood basophil histamine release. J Allergy Clin Immunol 99:87-93
Busse, W W; Gern, J E; Dick, E C (1997) The role of respiratory viruses in asthma. Ciba Found Symp 206:208-13; discussion 213-9
Jarjour, N N; Calhoun, W J; Kelly, E A et al. (1997) The immediate and late allergic response to segmental bronchopulmonary provocation in asthma. Am J Respir Crit Care Med 155:1515-21
Busse, W W; Gern, J E (1997) Viruses in asthma. J Allergy Clin Immunol 100:147-50

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