title: Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity.
abstract: To cause food-borne botulism, botulinum neurotoxin (BoNT) in the gastrointestinal lumen must traverse the intestinal epithelial barrier. However, the mechanism by which BoNT crosses the intestinal epithelial barrier remains unclear. BoNTs are produced along with one or more non-toxic components, with which they form progenitor toxin complexes (PTCs). Here we show that serotype A1 L-PTC, which has high oral toxicity and makes the predominant contribution to causing illness, breaches the intestinal epithelial barrier from microfold (M) cells via an interaction between haemagglutinin (HA), one of the non-toxic components, and glycoprotein 2 (GP2). HA strongly binds to GP2 expressed on M cells, which do not have thick mucus layers. Susceptibility to orally administered L-PTC is dramatically reduced in M-cell-depleted mice and GP2-deficient (Gp2(-/-)) mice. Our finding provides the basis for the development of novel antitoxin therapeutics and delivery systems for oral biologics.
authors: Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Takuhiro
authors: T
authors: Matsumura
authors: Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Yo
authors: Y
authors: Sugawara
authors: Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Masahiro
authors: M
authors: Yutani
authors: Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Sho
authors: S
authors: Amatsu
authors: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Department of Veterinary Sciences, School of Life and Environmental Science, Osaka Prefecture University, 1-58, Rinku-oraikita, Izumisano, Osaka 598-8531, Japan.
authors: Tomoko
authors: T
authors: Kohda
authors: School of Culture and Creative Studies, Aoyama Gakuin University, Tokyo 150-8366, Japan.
authors: Shin-Ichi
authors: S
authors: Fukuoka
authors: Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors: Yutaka
authors: Y
authors: Nakamura
authors: Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medial Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors: Shinji
authors: S
authors: Fukuda
authors: Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors: Koji
authors: K
authors: Hase
authors: 1] Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medial Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan [2] Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan [3] Department of Immune Regulation, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Hiroshi
authors: H
authors: Ohno
authors: Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Yukako
authors: Y
authors: Fujinaga
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000737:chemistry*; D002241:Carbohydrates / Q000737:chemistry; D003014:Clostridium botulinum; D003713:Dendritic Cells / Q000166:cytology; D004285:Dogs; D004705:Endocytosis; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000737:chemistry; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry
chemical_list: D002241:Carbohydrates; C489339:GP2 protein, human; D058851:GPI-Linked Proteins; C495998:Gp2 protein, mouse; D006388:Hemagglutinins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D019274:Botulinum Toxins, Type A; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase