CpG-ODN administration abolishes airway inflammation and remodeling in acute models of allergic airway disease. Herein, we investigated the therapeutic effect of CpG-ODN in a chronic fungal model of asthma. TLR9+/+ and TLR9-/- mice were sensitized to soluble A. fumigatus antigens and challenged with live A. fumigatus conidia. Mice were treated with intraperitoneal (IP) CpG, intranasal (IN) CpG, or left untreated from days 14 to 28-post conidia challenge. All features of allergic airway disease were attenuated in TLR9+/+ mice treated with IN CpG, including airway hyperresponsiveness (AHR), mucus production, and peribronchial fibrosis. TLR9-/- mice treated with IN CpG exhibited attenuated airway remodeling, but not AHR. Whole-lung IL-12 levels were significantly elevated in both TLR9+/+ and TLR9-/- mice receiving IN CpG but not in either group receiving IP CpG. Whole-lung IL-10 levels were significantly elevated in IN CpG-treated TLR9+/+ mice but not in TLR9-/- mice receiving IN CpG. Increased whole-lung transcript and protein levels of the scavenger receptors SR-A and MARCO were observed in TLR9-/- mice compared with TLR9+/+ mice, possibly accounting for the CpG responsiveness in the knockout group. Together, these data show that IN CpG has a therapeutic effect during established fungal asthma, which is TLR9-dependent and independent.

This work was financially supported, in part, by the NIH (grant HL069865 to CMH).