title: FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection.
abstract: The immune mechanisms that recognize inhaled Aspergillus fumigatus conidia to promote their elimination from the lungs are incompletely understood. FleA is a lectin expressed by Aspergillus fumigatus that has twelve binding sites for fucosylated structures that are abundant in the glycan coats of multiple plant and animal proteins. The role of FleA is unknown: it could bind fucose in decomposed plant matter to allow Aspergillus fumigatus to thrive in soil, or it may be a virulence factor that binds fucose in lung glycoproteins to cause Aspergillus fumigatus pneumonia. Our studies show that FleA protein and Aspergillus fumigatus conidia bind avidly to purified lung mucin glycoproteins in a fucose-dependent manner. In addition, FleA binds strongly to macrophage cell surface proteins, and macrophages bind and phagocytose fleA-deficient (∆fleA) conidia much less efficiently than wild type (WT) conidia. Furthermore, a potent fucopyranoside glycomimetic inhibitor of FleA inhibits binding and phagocytosis of WT conidia by macrophages, confirming the specific role of fucose binding in macrophage recognition of WT conidia. Finally, mice infected with ΔfleA conidia had more severe pneumonia and invasive aspergillosis than mice infected with WT conidia. These findings demonstrate that FleA is not a virulence factor for Aspergillus fumigatus. Instead, host recognition of FleA is a critical step in mechanisms of mucin binding, mucociliary clearance, and macrophage killing that prevent Aspergillus fumigatus pneumonia.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Sheena C
authors.initials: SC
authors.lastname: Kerr
authors.affiliation: Department of Genetics, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Fischer
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Meenal
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Center for Synthesis and Chemical Biology, University College Dublin, Dublin, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: McCabe
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: Tsokyi
authors.initials: T
authors.lastname: Choera
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: Fang Yun
authors.initials: FY
authors.lastname: Lim
authors.affiliation: Faculty of Science and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wimmerova
authors.affiliation: Veterinary Science Centre, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Carrington
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Center for Synthesis and Chemical Biology, University College Dublin, Dublin, Ireland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
mesh_terms: D000328:Adult; D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology* / Q000472:pathogenicity; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005643:Fucose / Q000378:metabolism; D005656:Fungal Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D037102:Lectins / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009077:Mucins / Q000276:immunology* / Q000378:metabolism; D055732:Pulmonary Aspergillosis / Q000276:immunology* / Q000378:metabolism; D013172:Spores, Fungal / Q000276:immunology
chemical_list: D005656:Fungal Proteins; D037102:Lectins; D009077:Mucins; C027112:fucose-binding lectin; D005643:Fucose