Viral respiratory infections (VRI) are detected in 70-90% of exacerbations of childhood asthma, and yet the majority of VRI in children with asthma do not cause exacerbaations. These paradoxical observations indicate that VRI contribute to exacerbations, but by themselves are usually not sufficient to provoke acute asthma. Previous studies by our group and others indicate that risk factors related to the host and virus contribute to but incompletely explain this discrepancy. Notably, we have new preliminary evidence that bacterial pathogens {Moraxella catarrhalis, Hemophilus influenza and Streptococcus pneumoniae) can increase the severity of viral respiratory illnesses, and these data are supported by similar findings in young children in Europe. We now propose the hypothesis that both bacteria and viruses contribute to the severity of wheezing illnesses in children, and that dual infections with rhinoviruses (HRV) and specific bacterial pathogens (M. catarrhalis. H. influenza, and S. pneumoniae) promote more severe respiratory illnesses and exacerbations of asthma. To test this hypothesis and identify relevant mechanisms, we propose three specific aims. First, serial nasal lavage and sputum specimens obtained during uncomplicated colds and colds leading to exaceriDations of asthma will be analyzed for viruses and bacteria to determine whether dual infections work together to cause more severe illnesses and exacerbations. Second, to determine whether dual infections cause greater tissue damage and inflammatory responses, airway secretions obtained during single vs. dual infections will be analyzed for indicators of airway injury and neutrophilic inflammation. Finally, we will determine whether individual variations in serum vitamin D levels or vitamin D receptor {VDR) genetics influence bacterial growth in the airway during VRI, and consequently impact respiratory illness severity. The results of these experiments will provide new insights into interactions between viral and bacterial respiratory infections, as well as the pathogenesis of respiratory symptoms and exacerbations of asthma.

Public Health Relevance

Acute exacerbations account for much of the morbidity and cost associated with asthma, and yet current therapies aimed at treating chronic airway inflammation are only partially effective at prevention. Identification of how specific interactions between viruses and bacteria cause more severe illnesses could lead to new approaches for the prevention and treatment of wheezing illnesses and asthma exacerbations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070831-12
Application #
8743242
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
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