TY - JOUR
T1 - Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity
AU - Matsumura, Takuhiro
AU - Sugawara, Yo
AU - Yutani, Masahiro
AU - Amatsu, Sho
AU - Yagita, Hideo
AU - Kohda, Tomoko
AU - Fukuoka, Shin Ichi
AU - Nakamura, Yutaka
AU - Fukuda, Shinji
AU - Hase, Koji
AU - Ohno, Hiroshi
AU - Fujinaga, Yukako
N1 - Funding Information:
We would like to thank A. Sano, T. Yoshimura, K. Sasaki, C. Aoki and Dr K. Hosomi for technical assistance, and Dr S. Kozaki for providing botulinum toxins. This study was supported in part by the Japan Society for the Promotion of Science (JSPS) through the Funding Program for Next Generation World-Leading Researchers (NEXT Program) and by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (20790336, 21390128).
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/2/17
Y1 - 2015/2/17
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms7255
DO - 10.1038/ncomms7255
M3 - Article
C2 - 25687350
AN - SCOPUS:84923331924
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 6255
ER -