House dust mites are one of the commonest aeroallergens for bronchial asthma worldwide, and 50 - 85% of asthmatics are typically allergic to house dust mites. Mannose-rich glycans in extracts of the house dust mite, Dermatophagoides farinae (Df), activate the dendritic cell (DC)-specific C-type lectin receptor, Dectin-2, to generate cysteinyl leukotrienes, critical proinflammatory lipid mediators for asthma, and cytokines directed to T helper 17 cells. Mouse models show that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation. However, the structure of the responsible gylcans in Df and how Dectin-2 recognizes the ligands are unknown. We hypothesize that Dectin-2 is the critical sensing molecule for the initiation and promotion of immune responses to major household allergens in asthma.
Specific Aim1 is to determine the critical amino acid residues in Dectin-2 for recognizing mannose-rich glycan ligands in house dust mite allergen. Understanding of the ligand-binding mode of Dectin-2 should help the development of specific inhibitors although Dectin-2 inhibition may not be beneficial for host defense against fungi.
Specific Aim2 is to examine whether an engineered Dectin-2 carbohydrate-recognition domain(s) can compete to ameliorate house dust mite-induced allergic pulmonary inflammation in mouse models. Utilizing an engineered Dectin-2 carbohydrate-recognition domain(s) as a tool for capturing allergen-associated ligands for DC activation may be better for new therapy.

Public Health Relevance

This project will determine the mechanism by which a C-type lectin receptor called Dectin-2 recognizes house dust mite allergen, a critical process of the initiation of asthma, by using mouse models and molecular biological approaches. Findings should provide new therapeutic strategy to asthma and other allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI107425-01
Application #
8569338
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Davidson, Wendy F
Project Start
2013-05-21
Project End
2015-04-30
Budget Start
2013-05-21
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$204,633
Indirect Cost
$87,133
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115