An orally applicable Shiga toxin neutralizer functions in the intestine to inhibit the intracellular transport of the toxin.
Shiga toxin 2 (Stx2) is a major virulence factor in infections with Stx-producing Escherichia coli (STEC), which causes 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 apparatus to the endoplasmic reticulum, a process 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.
Department of Molecular Life Sciences, Doshisha University, Tatara, Kyotanabe, Kyoto 610-0321, Japan.
Miho
M
Watanabe-Takahashi
Toshio
T
Sato
Taeko
T
Dohi
Noriko
N
Noguchi
Fumi
F
Kano
Masayuki
M
Murata
Takashi
T
Hamabata
Yasuhiro
Y
Natori
Kiyotaka
K
Nishikawa
D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism* / Q000382:microbiology*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D046509:Tissue Culture Techniques
C546398:Ac-PPP-tet; D010455:Peptides; D022641:Shiga Toxin 2