Molecular characterization of AfuFleA, an l-fucose-specific lectin from Aspergillus fumigatus

Kuboi, Satoshi; Ishimaru, Toshiyuki; Tamada, Sadao; Bernard, Edward M.; Perlin, David S.; Armstrong, Donald

doi:10.1007/s10156-013-0614-9

Cited by 19 publications

(18 citation statements)

References 29 publications

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“…[1] The criticali nitial stage of conidium adhesion to pneumocytes is partlym ediated by the recently identified fucose-binding lectin FleA (also called AFL). [2,3] FleA has been shown to exert as trong pro-inflammatory effect on human respiratory epithelial cells, [3] but its role as av irulent factor is controversial becausel ectin expressiona lso facilitates macrophage elimination and mucociliary clearance. [4,5] FleA formsh omodimers and its 3D structure, solved by X-ray crystallography,i ndicates that it adopts as ix-bladed b-propeller fold.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Lehot

Brissonnet

Dussouy

et al. 2018

Chemistry A European J

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FleA (or AFL), a fucose lectin, was recently identified in the opportunistic mold Aspergillus fumigatus, which causes fatal lung infections in immunocompromised patients. We designed di‐, hexa‐ and octavalent fucosides with various spacer arm lengths to block the hexameric FleA through chelation. Microcalorimetry measurements showed that the ethylene glycol (EG) spacer arm length has a strong influence on the binding affinity of the divalent fucosides. The relationship between the EG length and chelate binding efficiency to FleA was explored according to polymer theory. Hexa‐ and octavalent compounds based on cyclodextrin and octameric silsesquioxane scaffolds were nanomolar FleA inhibitors, surpassing their monovalent fucose analogue by more than three orders of magnitude. Importantly, some of the fucosides were highly efficient in preventing fungal spore adhesion to bronchoepithelial cells, with half maximal inhibitory concentration values in the micromolar range. We propose that the synergistic antiadhesive effect observed can be ascribed to chelate binding to FleA and to the formation of conidium aggregates, as observed by optical microscopy. These fucosides are promising tools that can be used to better understand the role of FleA in conidia pathogenicity and host defenses against invasive aspergillosis.

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Section: Introductionmentioning

confidence: 99%

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Lehot

Brissonnet

Dussouy

et al. 2018

Chemistry A European J

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“…This structure is compatible with the rodlet, which are constructed from stacked β‐sheets between antiparallel RodA hydrophobins . The cylindrical shape of AFL monomers with a 51 Å maximal outer diameter and a height of 40 Å means they could also fit in the space (≈5 nm) between two rodlets . The adhesion force histogram generated from the “true” adhesion map shows two well‐defined maxima, the first at 48 ± 13 pN which is attributed to the rupture of single fucose–lectin interactions, while the second at 95 ± 15 pN reflects double recognition events (Figure c).…”

Section: Resultsmentioning

confidence: 74%

“…AFL monomers could either be embedded within the rodlets or located between neighboring rodlets. The AFL monomer is composed of six blades, each formed of four antiparallel β‐sheets . This structure is compatible with the rodlet, which are constructed from stacked β‐sheets between antiparallel RodA hydrophobins .…”

Section: Resultsmentioning

confidence: 98%

“…Although RodA hydrophobins could be involved in the adhesion of conidia to host cells via hydrophobic forces, the molecular mechanisms governing the conidial adhesion remain poorly understood . Recently, the existence of the lectin AFL, namely, A. fumigatus fucose‐specific lectin, was proven with a high probability to be localized at the surface of A. fumigatus conidia . AFL possesses six binding sites able to bind l ‐fucose, a carbohydrate widely present on oligosaccharide epitopes on human tissues.…”

Section: Introductionmentioning

confidence: 99%

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Nanoscale Mapping of Multiple Lectins on Cell Surfaces by Single‐Molecule Force Spectroscopy

2017

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Molecular recognition events driven by protein–carbohydrate interactions play fundamental roles in various physiological and pathological processes in living organisms, including cohesion inside tissues, innate immune response, cancer cell metastasis, and infections. Unlike widely investigated carbohydrates, detailed knowledge of both the spatial organization of specific lectins and their identification on cell surfaces remains an essential prerequisite for the understanding of pathogen adhesion to host tissues and subsequent infection prevention. In this study, the spatially resolved localization, identification, and quantification of multiple carbohydrate‐binding sites are directly revealed on the surface of fungal pathogen Aspergillus fumigatus. Nanoscale reconstructed mapping from several recognition maps, corresponding each to a unique specific interaction probed by single‐molecule force spectroscopy, shows the distribution of carbohydrate‐binding sites on the pathogen surface. The identified binding sites are then blocked with the appropriate carbohydrate, attesting the possibility to control lectin‐mediated host–pathogen interactions. Germination markedly affects both the spatial distribution of carbohydrate‐binding sites, mostly expressed at the apex of hyphae, and the identity of the predominant ones, which depend on the location on germ tubes. These insights clearly open exciting avenues in nanomedicine to control host–pathogen interactions with the development of vaccines or inhibitory drugs that preferentially target the identified carbohydrate‐binding sites.

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“…FleA was subsequently identified in protein extracts of an A. fumigatus strain isolated from a cancer patient based on hemagglutination activity against rat erythrocytes [54]. in-depth investigations of membrane-associated adhesins [15].…”

Section: Using Bioinformatic Analyses Upadhyay Et Al Identified Putmentioning

confidence: 99%

Proteomic analysis of Aspergillus fumigatus – clinical implications

Moloney

Owens

Doyle

2016

Expert Review of Proteomics

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The traits that make A. fumigatus a successful colonizer and pathogen of humans are multi-factorial. Thus, a global investigative approach is required to elucidate the mechanisms utilized by the fungus to cause disease. Expert commentary: In doing so, a better understanding of disease pathology can be achieved with improved therapeutic/diagnostic solutions, thereby improving patient outcome. Proteomic analysis permits such investigations and recent work has yielded insight into these mechanisms.

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Molecular characterization of AfuFleA, an l-fucose-specific lectin from Aspergillus fumigatus

Cited by 19 publications

References 29 publications

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Nanoscale Mapping of Multiple Lectins on Cell Surfaces by Single‐Molecule Force Spectroscopy

Proteomic analysis of Aspergillus fumigatus – clinical implications

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