Abstract
Botulinum neurotoxins (BoNTs) are potent bacterial toxins. The high oral toxicity of BoNTs is largely attributed to the progenitor toxin complex (PTC), which is assembled from BoNT and nontoxic neurotoxin-associated proteins (NAPs) that are produced together with BoNT in bacteria. Here, we performed ex vivo studies to examine binding of the highly homogeneous recombinant NAPs to mouse small intestine. We also carried out the first comprehensive glycan array screening with the hemagglutinin (HA) component of NAPs. Our data confirmed that intestinal binding of the PTC is partly mediated by the HA moiety through multivalent interactions between HA and host carbohydrates. The specific HA-carbohydrate recognition could be inhibited by receptor-mimicking saccharides.
Highlights
Botulinum neurotoxins (BoNTs) are among the most life threatening natural substances to man, which have been designated as the Tier 1 select agents by the Centers for Disease Control and Prevention (CDC) [1,2]
There are eight major serotypes of BoNTs [6,7], which are produced in bacteria together with non-toxic neurotoxin-associated proteins (NAPs) in the form of progenitor toxin complex (PTC) [8]
We have previously shown that BoNT/A and non-toxic non-hemagglutinin (NTNHA) form an interlocked minimally functional complex (M-PTC/12S complex), in which BoNT is protected by NTNHA against digestive proteases and the acidic environment of the GI tract [16]
Summary
Botulinum neurotoxins (BoNTs) are among the most life threatening natural substances to man, which have been designated as the Tier 1 select agents by the Centers for Disease Control and Prevention (CDC) [1,2]. Toxins 2014, 6 from the gastrointestinal (GI) tract to the general circulation They invade motoneurons at neuromuscular junctions and cleave the soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) complex, which subsequently inhibits neurotransmitter release and paralyzes the affected muscles [3,4,5]. There are eight major serotypes (termed A–H) of BoNTs [6,7], which are produced in bacteria together with non-toxic neurotoxin-associated proteins (NAPs) in the form of progenitor toxin complex (PTC) [8]. Previous in vitro biophysical and biochemical studies suggested that the HA complex enhances intestinal absorption of the toxin complex by enriching PTCs on the cell surface through multivalent binding with carbohydrates [17].
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