Our log range goal is to understand the mechanisms by which respiratory virus infections cause airway hyperactivity and exacerbate asthma. Although the mechanisms of airway hyperresponsiveness associated with respiratory viral illnesses are not established, present evidence strongly suggests the virus effects on respiratory structure, immune function and the inflammatory response are important to the pathogenesis of bronchial hyperactivity and asthma. From observations with human leukocytes, and pigheadedness experimentally infected with rhinovirus, we hypothesize that viral respiratory infection enhances alveolar macrophage and pulmonary most cell effector function, and perturbs T or B cell responses, which collectively contribute to airway inflammation, bronchial hyperresponsiveness, and increased asthma. In the first specific aim, patients with allergic rhinitis and asthma will be experimentally infected wt rhinovirus 16 [RV 16], and patterns of airway reactivity will be determined in relationship to antigen provocation and concurrent mediator release into the circulating. This approach is necessary and important, as it will establish the effects of URI on airway function without airway instrumentation. The second specific aim under the same experimental conditions, will directly evaluate airway biology during RV 16 URI by bronchoalveolar lavage (BAL). In particular we will examine alveolar macrophage function, the role of lymphokines, subsets of lymphocytes, produce cell lines or clones, and determine which cells are virally infected by using antibody or in situ hybridization techniques. We propose that the importance of observations from BAL will be greater if correlated with measures of airway function which have not been complicated by instrumentation. From these experiments we will learn the biology of the airway response to viral infections and establish the mechanisms which cause airway hyperactivity and participate in asthma pathogenesis. Further we hope to show that no single cell, or abnormality, reactivity in viral respiratory infections. Rather, viral respiratory illnesses cause airway injury and hyperresponsiveness through a complex interaction of direct cytopathic properties of the virus and an integrated effect on respiratory cells and tissues which results in inflammation and thus bronchial hyperresponsiveness and obstruction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026609-02
Application #
3140417
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-09-01
Project End
1993-06-30
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Jarjour, N N; Gern, J E; Kelly, E A et al. (2000) The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 105:1169-77
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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