Botulinum neurotoxin A complex recognizes host carbohydrates through its hemagglutinin component

Area of Science:

• Microbiology
• Toxicology
• Biochemistry

Background:

• Botulinum neurotoxins (BoNTs) are highly potent bacterial toxins responsible for botulism.
• The oral toxicity of BoNTs is linked to the progenitor toxin complex (PTC), comprising BoNT and associated proteins (NAPs).
• Nontoxic neurotoxin-associated proteins (NAPs) play a role in BoNT oral toxicity, but their intestinal interactions are not fully understood.

Purpose of the Study:

• To investigate the binding mechanisms of NAPs to the mouse small intestine.
• To characterize the role of the hemagglutinin (HA) component of NAPs in intestinal binding.
• To identify specific host-molecule interactions involved in PTC intestinal adhesion.

Main Methods:

• Ex vivo studies using recombinant NAPs and mouse small intestine tissue.
• Comprehensive glycan array screening of the HA component of NAPs.
• Inhibition assays using receptor-mimicking saccharides.

Main Results:

• Recombinant NAPs demonstrated binding to the mouse small intestine in ex vivo studies.
• The hemagglutinin (HA) moiety of NAPs was identified as a key factor in intestinal binding.
• Multivalent interactions between HA and host carbohydrates were confirmed as the primary binding mechanism.
• Specific HA-carbohydrate recognition was inhibited by receptor-mimicking saccharides.

Conclusions:

• The hemagglutinin component of nontoxic neurotoxin-associated proteins mediates the intestinal binding of botulinum progenitor toxin complexes.
• This binding occurs through multivalent interactions with host carbohydrates on the intestinal surface.
• Targeting these HA-carbohydrate interactions with specific saccharides presents a potential strategy to inhibit botulinum toxin oral absorption and toxicity.