FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection

PLoS Pathogens

Orla McCabe¹  Stefan Oscarson¹  Gregory J. Fischer²  Clifford A. Lowell³  Meenal Sinha³  Fang Yun Lim⁴  Jonathan M. Palmer⁴  Tsokyi Choera⁴  Nancy P. Keller⁴  Sheena C. Kerr⁵  Shaopeng Yuan⁵  John V. Fahy⁵  Michaela Wimmerova⁶  Stephen D. Carrington⁷ 

[1] Center for Synthesis and Chemical Biology, University College Dublin, Dublin, Ireland;Department of Genetics, University of Wisconsin, Madison, Madison, Wisconsin;Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California;Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Madison, Wisconsin;Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California;Faculty of Science and Central European Institute of Technology, Masaryk University, Brno, Czech Republic;Veterinary Science Centre, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin, Ireland

关键词: Fleas;    Aspergillus fumigatus;    Mucin;    Macrophages;    Phagocytosis;    Alveolar macrophages;    Aspergillus flavus;    Lectins;   

DOI  :  10.1371/journal.ppat.1005555

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY