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Antibodies disrupt bacterial adhesion by ligand mimicry and allostery

ABSTRACT: Many microorganisms attach to host cells using lectins that bind surface glycans, a critical step in infections that makes lectins promising antimicrobial targets. FimH, the adhesin on Type 1 E. coli fimbriae, is a lectin that specifically binds the terminal mannose in glycans on the surfaces of host cells. Upon glycan binding, FimH transitions from the low affinity conformation to a high affinity conformation that can act as a catch-bond. Previous studies generated a polyclonal antibody response against FimH, where monoclonal antibodies from the pool targets different epitopes, including the glycan-binding pocket and key allosteric sites. However, the effector mechanisms of these antibodies remain unclear. Here, we use cryoEM paired with mass spectrometry, binding assays, and molecular dynamics simulations to determine the structure-function relationships underlying antibody-FimH binding. Our study reveals four distinct antibody mechanisms: ligand mimicry by an N-linked glycan on the antibody, direct occlusion of the open ligand pocket, FimH conformational arrest, and ligand trapping through long-range allosteric effects. Incorporation of antibody glycans into the antigen binding interface to mimic native ligands may be a general strategy for targeting lectins involved in host attachment. These structures reveal multiple mechanisms of host antibody responses to an allosteric protein, and provide blueprints for new antimicrobials against adhesins.

INSTRUMENT(S):

ORGANISM(S): Escherichia Coli

SUBMITTER: Tim S Veth

LAB HEAD: Nicholas M Riley

PROVIDER: PXD057683 | Pride | 2025-10-29

REPOSITORIES: Pride

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			Action	DRS
	21_deglyco_chymo.byrslt	Other
	21_deglyco_trypsin.byrslt	Other
	21_glyco_chymo.byrslt	Other
	21_glyco_trypsin.byrslt	Other
	24-09-20_SA_21_gold_average.raw	Raw

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Project description:Glycans are key to host-pathogen interactions, whereby recognition by the host and immunomodulation by the pathogen can be mediated by carbohydrate binding proteins, such as lectins of the innate immune system, and their glycoconjugate ligands. Previous studies have shown that excretory-secretory products of the porcine nematode parasite Trichuris suis exert immunomodulatory effects in a glycan-dependent manner. To better understand the mechanisms of these interactions, we prepared N-glycans from T. suis and both analyzed their structures and used them to generate a natural glycan microarray. With this array we explored the interactions of glycans with C-type lectins, C-reactive protein and sera from T. suis infected pigs. Glycans containing LacdiNAc and phosphorylcholine-modified glycans were associated with the highest binding by most of these proteins. In-depth analysis revealed not only fucosylated LacdiNAc motifs with and without phosphorylcholine moieties, but phosphorylcholine-modified mannose and N-acetylhexosaminesubstituted fucose residues, in the context of maximally tetraantennary N-glycan scaffolds. Furthermore, O-glycans also contained fucosylated motifs. In summary, the glycans of T. suis are recognized by both the innate and adaptive immune systems, and also exhibit species-specific features distinguishing its glycome from those of other nematodes.Glycans are key to host-pathogen interactions, whereby recognition by the host and immunomodulation by the pathogen can be mediated by carbohydrate binding proteins, such as lectins of the innate immune system, and their glycoconjugate ligands. Previous studies have shown that excretory-secretory products of the porcine nematode parasite Trichuris suis exert immunomodulatory effects in a glycan-dependent manner. To better understand the mechanisms of these interactions, we prepared N-glycans from T. suis and both analyzed their structures and used them to generate a natural glycan microarray. With this array we explored the interactions of glycans with C-type lectins, C-reactive protein and sera from T. suis infected pigs. Glycans containing LacdiNAc and phosphorylcholine-modified glycans were associated with the highest binding by most of these proteins. In-depth analysis revealed not only fucosylated LacdiNAc motifs with and without phosphorylcholine moieties, but phosphorylcholine-modified mannose and N-acetylhexosaminesubstituted fucose residues, in the context of maximally tetraantennary N-glycan scaffolds. Furthermore, O-glycans also contained fucosylated motifs. In summary, the glycans of T. suis are recognized by both the innate and adaptive immune systems, and also exhibit species-specific features distinguishing its glycome from those of other nematodes.

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Antibodies disrupt bacterial adhesion by ligand mimicry and allostery

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