Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity

Takuhiro Matsumura, Yo Sugawara, Masahiro Yutani, Sho Amatsu, Hideo Yagita, Tomoko Kohda, Shin-Ichi Fukuoka, Yutaka Nakamura, Shinji Fukuda, Koji Hase, Hiroshi Ohno () and Yukako Fujinaga ()
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Takuhiro Matsumura: 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
Yo Sugawara: 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
Masahiro Yutani: 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
Sho Amatsu: 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
Hideo Yagita: Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan
Tomoko Kohda: School of Life and Environmental Science, Osaka Prefecture University, 1-58, Rinku-oraikita, Izumisano, Osaka 598-8531, Japan
Shin-Ichi Fukuoka: School of Culture and Creative Studies, Aoyama Gakuin University
Yutaka Nakamura: Faculty of Pharmacy, Keio University
Shinji Fukuda: Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medial Sciences (IMS)
Koji Hase: Faculty of Pharmacy, Keio University
Hiroshi Ohno: Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medial Sciences (IMS)
Yukako Fujinaga: 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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7255

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