title: Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus.
abstract: Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Werner
authors.forename: Allison E
authors.initials: AE
authors.lastname: Metz
authors.forename: Dawn
authors.initials: D
authors.lastname: Horn
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hewitt
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schwiebert
authors.forename: Ines
authors.initials: I
authors.lastname: Faro-Trindade
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Chad
authors.initials: C
authors.lastname: Steele