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* Department of Medicine,
Department of Genetics, and
Department of Physiology, University of Alabama, Birmingham, AL 35294; and
Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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 β-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-1
, IL-1β, TNF-, CCL3/MIP-1, CCL4/MIP-1β, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust (to G.D.B.) and Cancer Association of South Africa (to G.D.B.); grants from the Parker B. Francis Foundation (to C.S.) and the American Lung Association (to C.S.); and Public Health Service Grant HL080317 (to C.S.).
2 Address correspondence and reprint requests to Dr. Chad Steele, Departments of Medicine and Microbiology, Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Alabama, 1900 University Boulevard, THT 437A, Birmingham, AL 35294. E-mail address: chadsteele{at}uab.edu
3 Abbreviations used in this paper: IPA, invasive pulmonary aspergillosis; BAL, bronchoalveolar lavage; PRR, pattern recognition receptor; ROS, reactive oxygen species; WT, wild type.
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T. R. T. Dagenais and N. P. Keller Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis Clin. Microbiol. Rev., July 1, 2009; 22(3): 447 - 465. [Abstract] [Full Text] [PDF]
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