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: Sheena C Kerr, Gregory J Fischer, Meenal Sinha, Orla McCabe, Jonathan M Palmer, Tsokyi Choera, Fang Yun Lim, Michaela Wimmerova, Stephen D Carrington, Shaopeng Yuan, Clifford A Lowell, Stefan Oscarson, Nancy P Keller, John V Fahy
• Journal: PLoS pathogens (PLoS Pathog) Vol. 12 Issue 4 Pg. e1005555 (Apr 2016) ISSN: 1553-7374 [Electronic] United States
• PMID: 27058347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fungal Proteins
• Lectins
• Mucins
• fucose-binding lectin
• Fucose

Topics

• Adult
• Animals
• Aspergillus fumigatus (immunology, pathogenicity)
• Blotting, Western
• Disease Models, Animal
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Fucose (metabolism)
• Fungal Proteins (immunology, metabolism)
• Humans
• Immunity, Mucosal (immunology)
• Lectins (immunology, metabolism)
• Macrophages (immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Mucins (immunology, metabolism)
• Pulmonary Aspergillosis (immunology, metabolism)
• Spores, Fungal (immunology)