The long-term goal of this proposal is to understand how respiratory viral infections lead to chronic hypersecretory airway diseases like asthma. The present proposal focuses on new findings related to the role of respiratory viruses in fine development of long-term goblet cell hyperplasia. This focus derives from our studies of mice and mouse tracheal epithelial cells successively defining that paramyxoviral infection produces not only acute bronchiolitis but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after viral clearance. This chronic response proceeds despite protection from acute airway infammation and hyperreactivity, and in contrast to allergen challenge, the chronic response persists indefinitely and is uninfluenced by IFN-gamma deficiency. Similar to allergen, the chronic response is at least partially prevented by glucocorticoid treatment. The virus-induced chronic response also exhibits genetic susceptibility allowing for the identification of candidate target genes by a combined genetic/microarray strategy. Memory for the chronic response appears to be contained in the adaptive immune system allowing for adoptive transfer in vivo and in vitro. In addition, we find similar phenotypic responses in human subjects with asthma. Thus, we propose that paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-ran strategy since viral effects persist after clearance). Further, each of these phenols (acute inflammation/hyperreactivity, chronic hyperreactivity, and chronic goblet cell hyperplasia) may be genetically segregated and therefore depend on distinct controls that appear critical for the development of lifelong airway diseases. Accordingly, we have the following specific aims: I. Use a mouse model of bronchiolitis to define how specific candidate genes control longterm virus-induced goblet cell hyperplasia and how immune cells mediate this response. Here, we develop a plan to identify and characterize our first candidate gene, i.e. mouse calcium-activated chloride channel (mCLCA3) as well as a specific immune cell subset, i.e., virus-specific CD8+ memory T cells. II. Use isolated airway epithelial cells to define the molecular basis for how specific candidate genes and immune cells cause goblet cell hyperplasia in coordination with Aim I. III Use healthy and asthmatic subjects in a glucocorticoid treatment-withdrawal model to define the relationship between goblet cell hyperplasia and the status of candidates from Aims I and II.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073159-04
Application #
7082091
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F1))
Program Officer
Punturieri, Antonello
Project Start
2003-07-01
Project End
2008-03-31
Budget Start
2006-07-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$373,511
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Byers, Derek E; Alexander-Brett, Jennifer; Patel, Anand C et al. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123:3967-82
Yurtsever, Zeynep; Sala-Rabanal, Monica; Randolph, David T et al. (2012) Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation. J Biol Chem 287:42138-49
Alevy, Yael G; Patel, Anand C; Romero, Arthur G et al. (2012) IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Invest 122:4555-68
Holtzman, Michael J; Patel, Dhara A; Zhang, Yong et al. (2011) Host epithelial-viral interactions as cause and cure for asthma. Curr Opin Immunol 23:487-94
Kim, Edy Y; Battaile, John T; Patel, Anand C et al. (2008) Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 14:633-40