Differential High-Affinity Interaction of Dectin-1 with Natural or Synthetic Glucans Is Dependent upon Primary Structure and Is Influenced by Polymer Chain Length and Side-Chain Branching

Abstract

Glucans are structurally diverse fungal biopolymers that stimulate innate immunity and are fungal pathogen-associated molecular patterns. Dectin-1 is a C-type lectin-like pattern recognition receptor that binds glucans and induces innate immune responses to fungal pathogens. We examined the effect of glucan structure on recognition and binding by murine recombinant Dectin-1 with a library of natural product and synthetic (133)-␤/(136)-␤-glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (133)-␤-linked backbone structure. Although Dectin-1 is highly specific for (133)-␤-D-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (133)-␤-D-glucans over a very wide range of binding affinities (2.6 mM-2.2 pM). One of the most striking observations that emerged from this study was the remarkable high-affinity interaction of Dectin-1 with certain glucans (2.2 pM). These data also demonstrated that synthetic glucan ligands interact with Dectin-1 and that binding affinity increased in synthetic glucans containing a single glucose side-chain branch. We also observed differential recognition of glucans derived from saprophytes and pathogens. We found that glucan derived from a saprophytic yeast was recognized with higher affinity than glucan derived from the pathogen Candida albicans. Structural analysis demonstrated that glucan backbone chain length and (136)-␤ side-chain branching strongly influenced Dectin-1 binding affinity. These data demonstrate: 1) the specificity of Dectin-1 for glucans; 2) that Dectin-1 differentiates between glucan ligands based on structural determinants; and 3) that Dectin-1 can recognize and interact with both natural product and synthetic glucan ligands.

Eng1 and Exg8 Are the Major α-Glucanases Secreted by the Fungal Pathogen Histoplasma capsulatum

“…This indicates hydrolysis of cell wall ␤-glucans by Eng1 is sufficient to render them undetectable by Dectin-1 without requiring the remaining mono-or disaccharide exposed termini to be hydrolyzed by Exg8. This model fits with the described ligand specificity of Dectin-1 being oligosaccharides of at least seven glucose units (29).…”

β-(1,3)-Glucan Exposure Assessment by Passive Airborne Dust Sampling and New Sensitive Immunoassays

“…Because they are typical microbe-associated molecular patterns (MAMPs), ␤-(1,3)-glucans activate cells of the innate immune system by binding to glucan-specific receptors like dectin-1 (1,4,6) and other cellular membrane receptors (5,21). Associations between indoor ␤-(1,3)-glucan exposure and inflammatory reactions of the respiratory system have been reported (3,10,25,33,34,40), but protective effects of glucan exposure in early childhood against the development of asthma and allergy have also been suggested (9,13,15,29).…”

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

“…Dectin-1 binds to the glucose polymer laminarin that is similar to the sugar moiety found in fungal walls but does not bind to mannan, the mannose polymer derived from Saccharomyces cerevisiae (30). D-CAR + T cells exhibited the same binding preference, because laminarin, but not mannan, abrogated binding of mAb specific for Dectin-1 to D-CAR on genetically modified T cells in a dose-dependent manner ( Fig.…”