Rhinovirus (RV) is an important pathogen present in the respiratory tract epithelium of a significant proportion of asthma patients during severe pulmonary exacerbations. Mechanisms by which the human respiratory tract epithelium identifies acute RV infection, mechanisms used immediately by the human respiratory tract epithelium to respond to this infection, and how these mechanisms are impaired in asthmatics have not been fully elucidated. Our recent studies of DUOX2 suggest this protein is critical for normal antiviral host defense. We hypothesize that DUOX2 is a central component for host defense against RV infection in respiratory tract epithelium: When activated by RV, DUOX2 produces hydrogen peroxide (H2O2), hypohalous acid, or reactive nitrogen species to (a) directly inactivate rhinovirus and (b) stimulate the expression of early antiviral genes, but (c) antiviral activity is suppressed in the presence of Th2 cytokines such as interleukin-4 (IL- 4) or interleukin-13 (IL-13).
Specific Aims : Test the predictions that (1) DUOX2-mediated generation of H2O2, hypohalous acids, or reactive nitrogen species directly inactivates RV, (2) DUOX2- mediated generation of H2O2 results in the early activation of antiviral genes, and (3) IL-4 blocks DUOX2-mediated antiviral activity by inhibiting transcriptionally-mediated DUOX2 expression. We will use human respiratory tract epithelial cells for all the studies outlined for this project. Relevance to Public Health - Rhinovirus (RV) is an important pathogen present in the respiratory tract epithelium of a significant proportion of asthma patients during severe pulmonary exacerbations. Our recent studies of DUOX2 suggest this protein is critical for normal antiviral host defense. We anticipate our studies will reveal novel mechanisms by which the respiratory tract epithelium activates innate host defense against RV infection. These studies will potentially elucidate specific mechanisms that are impaired in asthmatic patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085311-05
Application #
8215722
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Noel, Patricia
Project Start
2008-02-01
Project End
2014-07-31
Budget Start
2012-02-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$338,580
Indirect Cost
$115,830
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Chang, Sandra; Linderholm, Angela; Franzi, Lisa et al. (2013) Dual oxidase regulates neutrophil recruitment in allergic airways. Free Radic Biol Med 65:38-46
Price, David; Harper, Richart; Henderson, Mark C (2013) Progressive cervical myelopathy as presentation of sarcoidosis. J Gen Intern Med 28:855-6
Linderholm, Angela Lee; Onitsuka, June; Xu, Changhong et al. (2010) All-trans retinoic acid mediates DUOX2 expression and function in respiratory tract epithelium. Am J Physiol Lung Cell Mol Physiol 299:L215-21
Hill 3rd, Thomas; Xu, Changhong; Harper, Richart W (2010) IFNgamma mediates DUOX2 expression via a STAT-independent signaling pathway. Biochem Biophys Res Commun 395:270-4