FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection.
FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection.
复制标题
烟曲霉中的FleA表达通过粘蛋白和巨噬细胞上的岩藻糖基化结构识别，以防止肺部感染。
DOI：
10.1371/journal.ppat.1005555
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Fahy JV
中科院分区：
文献类型：
--
作者：
Kerr SC;Fischer GJ;Sinha M;McCabe O;Palmer JM;Choera T;Lim FY;Wimmerova M;Carrington SD;Yuan S;Lowell CA;Oscarson S;Keller NP;Fahy JV
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. Inhaled Aspergillus fumigatus conidia are effectively eliminated from the lung by the coordinated actions of mucociliary clearance and macrophage killing, but the mechanisms of attachment of Aspergillus fumigatus (A. fumigatus) conidia to the airway mucus gel are unknown. In addition, the mechanisms of phagocytosis of conidia by macrophages are incompletely understood, because inhibition of Dectin-1, mannose receptor, and TLR-2/4 does not completely prevent phagocytosis. A fucose-binding lectin (FleA) expressed on the surface of Aspergillus conidia has recently been described, but its function is unknown. In order to reveal FleA’s function, we carried out combined in vitro and in vivo studies using several novel reagents, including recombinant FleA, FleA deficient (∆fleA) conidia and a potent fucopyranoside inhibitor of FleA. In vitro studies found that FleA mediates binding of A. fumigatus conidia to airway mucins and phagocytosis of conidia by lung macrophages. In in vivo studies we found that mice infected with ∆fleA conidia develop invasive aspergillosis whereas those exposed to WT conidia do not. Based on our findings, we propose a novel host defense mechanism against A. fumigatus in which FleA expression on conidia is recognized by lung mucins and macrophages to promote mucociliary clearance and macrophage killing and protect from invasive pulmonary aspergillosis.
