Modulation of Dectin-2 as a Therapeutic Approach to Dust Mite-Elicited Asthma

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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.