|Lee, Kwangkook - University Of California|
|Lam, Kwok-ho - University Of California|
|Kruel, Anna - University Of Hannover|
|Mahrhold, Stefan - University Of Hannover|
|Perry, Kay - Cornell University - New York|
|Cheng, Luisa Wai Wai|
|Rummel, Andreas - University Of Hannover|
|Jin, Rongsheng - Cornell University - New York|
Submitted to: Toxicon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/4/2015
Publication Date: 8/10/2015
Publication URL: http://handle.nal.usda.gov/10113/63148
Citation: Lee, K., Lam, K., Kruel, A.M., Mahrhold, S., Perry, K., Cheng, L.W., Rummel, A., Jin, R. 2015. Inhibiting oral intoxication of botulinum neurotoxin A by carbohydrate receptor mimics. Toxicon. 107:43-49. doi: org/10.1016/j.toxin2015.08.003.
Interpretive Summary: Botulinum neurotoxins (BoNT) are some of the most potent biological toxins. They form large protein complexes that must cross the intestinal barriers to reach the bloodstream. This study identified sugars that bind components of the toxin complex. These sugars are shown to inhibit entry of botulinum neurotoxin in both cultured cells and in the mouse. Understanding the mechanism of how these large toxin complexes cross intestinal barriers will advance our understanding of botulinum toxins and how to design effective therapeutic strategies.
Technical Abstract: Botulinum neurotoxins (BoNTs) cause the disease botulism manifested by flaccid paralysis that could be fatal to humans and animals. Oral ingestion of the toxin with contaminated food is one of the most common routes of BoNT intoxication, where BoNT assembles with several auxiliary proteins to survive in the gastrointestinal tract and subsequently bleaches into the general circulation. In this process, several hemagglutinin proteins form a multi-protein complex (the HA complex) that recognizes host glycans on the intestinal epithelial cell surface to facilitate BoNT absorption. Blocking carbohydrate binding to the HA complex could significantly inhibit the oral toxicity of BoNT. Here, we identify lactulose, a galactose-containing non-digestible sugar commonly used to treat constipation, as a prototype inhibitor against oral BoNT/A intoxication. As revealed by a crystal structure, lactulose binds to the HA complex at the same site where the host galactose-containing carbohydrate receptors bind. In vitro assay using intestinal Caco-2 cells demonstrated that lactulose inhibits HA from compromising the integrity of the epithelial cell monolayers and blocks the transportation of HA. Furthermore, co-administration of lactulose significantly protected mice against BoNT/A oral intoxication in vivo. Taken together, these data encourage the development of carbohydrate receptor mimics as a therapeutic intervention to prevent and treat BoNT oral intoxication.