IAI Accepts, published online ahead of print on 26 October 2009

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Infect. Immun. doi:10.1128/IAI.01022-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

An orally applicable Shiga toxin-neutralizer functions in the intestine to inhibit the intracellular transport of the toxin

Miho Watanabe-Takahashi, Toshio Sato, Taeko Dohi, Noriko Noguchi, Fumi Kano, Masayuki Murata, Takashi Hamabata, Yasuhiro Natori, and Kiyotaka Nishikawa^*

Department of Molecular Life Sciences, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan; Department of Infectious Disease, Research Institute, International Medical center of Japan, Tokyo, Japan; Department of Gastroenterology, Research Institute, International Medical center of Japan, Tokyo, Japan; Department of Systems Life Sciences, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan; Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan; PRESTO, Japan Science and Technology Agent, Saitama, Japan; Department of Health Chemistry, School of Pharmacy, Iwate Medical University, Iwate, Japan

^* To whom correspondence should be addressed. Email: knishika{at}mail.doshisha.ac.jp.

Shiga toxin 2 (Stx2) is a major virulence factor of Stx-producing Escherichia coli (STEC) infections, which cause gastrointestinal diseases and sometimes fatal systemic complications. Recently, we developed an oral Stx2-inhibitor known as Ac-PPP-tet that exhibits remarkable therapeutic potency in an STEC-infection model. However, the precise mechanism underlying the in vivo therapeutic effects of Ac-PPP-tet is unknown. Here, we found that Ac-PPP-tet completely inhibited fluid accumulation in the rabbit ileum caused by the direct injection of Stx2. Interestingly, Ac-PPP-tet accumulated in the ileal epithelial cells only through its formation of a complex with Stx2. The formation of Ac-PPP-tet-Stx2 complexes in cultured epithelial cells blocked the intracellular transport of Stx2 from the Golgi to the endoplasmic reticulum, a route that is essential for Stx2 cytotoxicity. Thus, Ac-PPP-tet is the first Stx-neutralizer that functions in the intestine by altering the intracellular transport of Stx2 in epithelial cells.